3-(piperidinyl)-and 3-(pyrrolidinyl)-1H-indazoles

ABSTRACT

Novel 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles, intermediates and processes for the preparation thereof, and methods for treating psychoses, treating depression, alleviating pain, treating convulsions and treating hypertension utilizing compounds or compositions thereof are disclosed.

This is a division, of application Ser. No. 811,090 filed Dec. 19, 1985,now U.S. Pat. No. 4,670,447, which is a continuation-in-part of U.S.patent application Ser. No. 694,198 filed Jan. 23, 1985, now which is acontinuation-in-part of U.S. patent application Ser. No. 679,662 filedDec. 7, 1984, now abandoned, which in turn is a continuation-in-part ofU.S. patent application Ser. No. 525,088 filed Aug. 22, 1983 nowabandoned.

The present invention relates to novel 3-(piperidinyl)- and3-(pyrrolidinyl)-1H-indazoles. More particularly, the present inventionrelates to 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of formula1 ##STR1## wherein R is hydrogen, loweralkyl, loweralkenyl,lowercycloalkylloweralkyl, ##STR2## cyano, cyanomethyl, formyl,loweralkanoyl, diloweralkylphosphinylmethyl, ##STR3## R¹ is hydrogen,loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, ##STR4##diloweralkylaminoloweralkyl, cyano, cyanomethyl, formyl, loweralkanoyl,hydroxymethyl, hydroxyloweralkyl, lowercycloalkylloweralkanoyl,loweralkoxycarbonylloweralkyl, ##STR5## R⁵ CO, 2- or 4-pyridinyl or2-pyrimidinyl; R² and R^(2') are independently loweralkyl,2,2,2-trichloroethyl or phenyl; R³ and R⁴ are independently hydrogen orloweralkyl; R⁵ is a member selected from the group furyl, thienyl,pyridinyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, X, X' and X"are independently hydrogen, halogen, loweralkyl, loweralkoxy,loweralkanoyl loweralkylthio, cyano, carbamoyl, hydroxy, nitro, amino ortrifluoromethyl; Y is oxygen or sulfur; m is 2 or 3; n is 1 or 2; andthe sum of m and n is 3 or 4; n' and n" are independently 2 or 3; p, p'and p" are independently 1 or 2, except where X" is halogen p" is 1through 5; q and q' are independently 1, 2, 3 or 4; R⁶ is lower alkyl,aryl, aralkyl, cycloalkylloweralkyl, a loweralkyl substituted with anamino, e.g. -alkylene-NH₂, loweralkylamino, e.g. alkyl-NH-,diloweralkylamino, e.g. ##STR6## R⁷, R⁸ and R⁹ are independentlyhydrogen, loweralkyl or aryl; the optical antipode thereof, or thepharmaceutically acceptable acid addition salt thereof, which are usefulfor treating psychoses, treating depression, treating and alleviatingpain, treating hypertension and treating convulsions, alone or incombination with inert adjuvants.

Preferred 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of thepresent invention are those wherein R is hydrogen, loweralkyl, ##STR7##wherein X', p' and q are as above, ##STR8## and R¹ is hydrogen,loweralkyl, lowercycloalkylloweralkyl, loweralkanoyl, hydroxymethyl,hydroxyloweralkyl, ##STR9## wherein X" and p" are as above and q' is 1or R^(2') OCO wherein R^(2') is as above or ##STR10## wherein X" and p"are as above. Most preferred are these wherein R is hydrogen, ##STR11##and R¹ is ##STR12## wherein X", p" and q' are as above, hydrogen, loweralkyl, or ##STR13##

Subgeneric to the 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles ofthe present invention are compounds wherein:

(a) R is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkylor ##STR14## wherein X', p' and q are as above; (b) R is cyano orcyanomethyl;

(c) R is formyl, loweralkanoyl, ##STR15## wherein X', p' and q are asabove or R² OCO wherein R² is as above, the wherein R is as above and qis 1;

(d) R is ##STR16## wherein R³, R⁴, X', n' and p' are as above; (e) R is##STR17## wherein R³, X', n' and p' are as above; (f) R is ##STR18##wherein n' is as above; (g) R is ##STR19## wherein n' is as above; (h) Ris ##STR20## (i) R is ##STR21## (j) R¹ is hydrogen, loweralkyl,loweralkenyl, lowercycloalkylloweralkyl ##STR22## wherein X", p" and q'are as above; (k) R¹ is ##STR23## wherein X" and p" are as above; (l) R¹is diloweralkylaminoloweralkyl;

(m) R¹ is cyano or cyanomethyl;

(n) R¹ is formyl, loweralkanoyl, lowercycloalkyloweralkanoyl, ##STR24##wherein X", p" and q' are as above, or R^(2') OCO wherein R^(2') is asabove;

(o) R¹ is ##STR25## wherein n" is as above; (p) R¹ is ##STR26## whereinX" and p" are as above; (q) R¹ is 2- or 4-pyridinyl or 2-pyrimidinyl;

(r) R¹ is R⁵ CO wherein R⁵ is as above; and

(s) R¹ is hydroxymethyl or hydroxyloweralkyl.

As used through the specification and appended claims, the term "alkyl"refers to a straight or branched chain hydrocarbon radical containing nounsaturation and having 1 to 10 carbon atoms such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl,2-octyl, 3-nonyl, 4-decyl and the like; the term "alkenyl" refers to astraight or branched chain hydrocarbon radical having one olefinic bondand containing 3 to 10 carbon atoms such as 2-propenyl, 2-butenyl,3-pentenyl, 3-hexenyl, 3-heptenyl, 4-octenyl, 4-nonenyl, 5-decenyl andthe like; the term "cycloalkyl" refers to a saturated hydrocarbon grouppossessing at least one carbocyclic ring, the ring containing from 3 to10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclodecyl and the like; the term "alkanol"refers to a compound formed by a combination of an alkyl group and ahydroxy radical. Examples of alkanols are methanol, ethanol, 1- and2-propanol, 1,2-dimethylethanol, hexanol, octanol, decanol and the like.The term "alkoxy" refers to a radical formed by removal of the hydrogenatom from the hydroxy function of an alkanol. Examples of alkoxy aremethoxy, ethoxy, 1- and 2-propoxy, 1,2-dimethylethoxy, hexoxy, octoxy,decoxy, and the like. The term "alkanoic acid" to a compound formed bycombination of a carboxyl group with a hydrogen atom or alkyl group.Examples of alkanoic acids are formic acid, acetic acid, propanoic acid,2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid andthe like; the term "halogen" refers to a member of the family consistingof fluorine, chlorine, bromine or iodine. The term "alkanoyl" refers tothe radical formed by removal of the hydroxyl function from an alkanoicacid. Examples of alkanoyl groups are formyl, acetyl, propionyl,2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl and the like. The term"lower" as applied to any of the aforementioned groups refers to a grouphaving a carbon skeleton containing up to and including 7 carbon atoms.The term "alkylene" refers to a bivalent radical of the lower branchedor unbranched group it is derived from having valence bonds from twoterminal carbons thereof, e.g. ethylene (--CH₂ CH₂ --), propylene (--CH₂CH₂ CH₂ --), isopropylene ##STR27## etc. The term "aryl" refers toradical of the formula ##STR28## wherein X" and p" are as defined above.The term "aralkyl" refers to an aryl-loweralkyl radical wherein "aryl"and "loweralkyl" are as defined above.

The compounds of the present invention which lack an element of symmetryexist as optical antipodes and as the racemic forms thereof. The opticalantipode may be prepared from the corresponding racemic forms bystandard optical resolution techniques, involving, for example, theseparation of diasteromeric salts of those instant compoundscharacterized by the presence of a basic amino group and an opticallyactive acid, or by the synthesis from optically active precursors.

The present invention comprehends all optical isomers and racemic formsthereof of the compounds disclosed and claimed herein. The formulas ofthe compounds shown herein are intended to encompass all optical isomersof the compounds so depicted.

The novel 3-(piperidinyl) and 3-(pyrrolidinyl)-1H-indazoles of thepresent invention are synthesized by processes illustrated in ReactionSchemes A to C.

To prepare the 3-(piperidinyl)- or 3-(pyrrolidinyl)-1H-indazole systemof formula 1 wherein R is alkyl, a 1-alkylchloropiperidine 3 or a1-alkylchloropyrrolidine 3 is condensed with a 2-fluorobenzonitrile 4 toa 1-alkyl-(2-fluorobenzoyl)piperidine 5 or a1-alkyl-(2-fluorobenzoyl)pyrrolidine 5 which is cyclized to a3-(1-alkylpiperidinyl)- or a 3-(1-alkylpyrrolidinyl)-1H-indazole 8. SeeReaction Scheme A.

The condensation of a 1-alkylchloropiperidine 3 or a1-alkylchloropyrrolidine 3 with a 2-fluorobenzonitrile 4 is effected byconventional Grignard techniques. Typically, the benzonitrile 4,dissolved in an ethereal solvent, such as tetrahydrofuran, is treatedwith a Grignard reagent, prepared from the chloropiperidine 3 orchloropyrrolidine 3 and magnesium turnings in an ethereal solvent, suchas tetrahydrofuran, followed by hydrolysis under acidic conditions. Aninitiator such as ethyl bromide may be employed to facilitate formationof the Grignard reagent. The cyclization of a1-alkyl-(2-fluorobenzoyl)piperidine 5 or a1-alkyl-(2-fluorobenzoyl)pyrrolidine 5 to a3-(1-alkylpiperidinyl)-1H-indazole 8 or a3-(1-alkylpyrrolidinyl)-1H-indazole 8 is performed by treating thebenzoylpiperidine 5 or benzoylpyrrolidine 5 with hydrazine, generally asthe hydrate, at an elevated temperature and pressure within the range ofabout 100° to about 200° C., and about 200 to about 300 psi,respectively. A cyclization temperature of about 150° C. is preferred. Acyclization pressure of about 250 psi is also preferred.

To synthesize the 3-(piperidinyl)- or 3-(pyrrolidinyl)-1H-indazolesystem of formula 1 wherein R is alkenyl, cycloalkylalkyl, ##STR29##cyanomethyl, ##STR30## wherein R³, X', n', p' and q are as above, a1-alkyl-(2-fluorobenzoyl)piperidine 5 or1-alkyl-(2-fluorobenzoyl)pyrrolidine 5 is converted to a1-phenoxycarbonyl-(2-fluorobenzoyl)piperidine 6 or1-phenoxycarbonyl-(2-fluorobenzoyl)pyrrolidine 6 followed by hydrolysisof the 1-phenoxycarbonylpiperidine 6 or 1-phenoxycarbonylpyrrolidine 6to a (2-fluorobenzoyl)piperidine 7 or (2-fluorobenzoyl)pyrrolidine 7,alkylation of the benzoylpiperidine 7 or benzoylpyrrolidine 7 to anN-substituted benzoylpiperidine 9 or N-substituted benzoylpyrrolidine 9and cyclization to the indazole 10 wherein R is as immediately above.See Reaction Schemes A and B.

The conversion of the 1-alkylpiperidine 5 or 1-alkylpyrrolidine 5 to thephenoxycarbonylpiperidine 6 or phenoxycarbonylpyrrolidine 6 isaccomplished by treating a tertiary amine 5 with phenylchloroformate inan aromatic solvent in the presence of an acid scavenger. Included amongaromatic solvents are benzene, toluene, xylene and the like. Toluene isthe preferred aromatic solvent. Included among acid scavengers aresodium carbonate, potassium carbonate and the like. Potassium carbonateis preferred. While the reaction temperature is not narrowly critical,it is preferred to conduct the conversion at the reflux temperature ofthe reaction mixture to assure a reasonable rate of formation of thecarbamate 6.

The hydrolysis of the phenoxycarbonylpiperidine 6 orphenoxycarbonylpyrrolidine 6 to the 1-unsubstituted piperidine 7 or1-unsubstituted pyrrolidine 7 is performed by methods well-known in theart, involving, for example, treatment of the carbamate 6 with anaqueous solution of an alkali metal hydroxide such as sodium hydroxideor potassium hydroxide at or about the reflux temperature of thereaction mixture. Aqueous potassium hydroxide is preferred.

The alkylation of an N-unsubstituted piperidine 7 or N-unsubstitutedpyrrolidine 7 to an N-substituted piperidine 9 wherein R is asimmediately above defined or an N-substituted pyrrolidine 9 wherein R isalso as immediately above defined is performed by means of an alkenyl,cycloalkylalkyl, or cyanomethyl halide, i.e. an iodide, bromide orchloride, or a compound of the formula ##STR31## wherein R³, X', n', p'and q are as above and Hal is iodo, bromo or chloro, in the presence ofa base suspended or dissolved in a polar aprotic solvent. Suitable basesinclude alkali metal carbonates and bicarbonates such as, for example,sodium and potassium carbonate and sodium and potassium bicarbonate.Suitable polar aprotic solvents include dimethylformamide,dimethylacetamide and hexamethylphosphoramide. Potassium carbonate anddimethylformamide are the preferred base and solvent. A reactionpromotor such as potassium iodide and an elevated reaction temperaturewithin the range of about 70° to about 120° C. may be employed tofacilitate the alkylation. A reaction temperature of about 90° C. ispreferred.

To furnish the 3-(piperidinyl)- or 3-(pyrrolidinyl)-1H-indazole offormula 1 wherein R is ##STR32## wherein n' is as above thecorresponding ethylene glycol cyclic ketal thereof, i.e., a compound offormula 1 wherein R is ##STR33## is hydrolyzed. The hydrolysis isconveniently accomplished by conventional methods involving, forexample, the interaction of a mineral acid, such as hydrochloric acid,in an alkanol, such as methanol, at ambient temperature, or an elevatedtemperature such as the reflux temperature of the reaction system.

To introduce the indol-3-ylalkyl function, i.e., to fabricate anN-substituted piperidine or N-substituted pyrrolidine of formula 1wherein R is a group of the formula ##STR34## wherein R³, R⁴, X', n' andp' are as above, one treats an N-unsubstituted piperidine 7 orN-unsubstituted pyrrolidine 7 with a 3-(phenylsulfonylalkyl)indole or3-(alkylphenylsulfonylalkyl)indole of the formula ##STR35## wherein Z isa group of the formula ##STR36## wherein Y' is hydrogen or alkyl and R³,R⁴, X', n' and p' are as above.

The reaction involving the displacement of the phenylsulfonyl group ofthe indole is accomplished by treating an N-unsubstituted piperidine 7or N-unsubstituted pyrrolidine 7 with the phenylsulfonylindole in anaprotic polar solvent, such as dimethylformamide, dimethylacetamide andhexamethylphosphoramide, or an alkanone such as acetone, 2-butanone,3-pentanone and the like, dimethylformamide and 2-butanone beingpreferred, in the presence of an acid scavenger such as an alkali metalcarbonate (sodium or potassium carbonate) or alkali metal bicarbonate(sodium or potassium bicarbonate), potassium carbonate and sodiumbicarbonate being preferred, at a temperature of about 70° to about 110°C., preferably a temperature of 90° C. when an aprotic polar solvent isused, and at about the reflux temperature of the reaction system when analkanone is employed as the solvent.

The cyclization of the N-substituted benzoylpiperidine 9 orN-substituted benzoylpyrrolidone 9 to the 1H-indazole 10 is readilyachieved by procedures substantially similar to those utilized for thecyclization of benzoylpiperidine 5 or benzoylpyrrolidine 5 to1H-indazole 8.

To prepare 1H-indazoles substituted at the 1-position, i.e., compoundsof formula 11 wherein R¹ is alkyl, alkenyl, cycloalkylalkyl,dialkylaminoalkyl, loweralkylcarbonylloweralkyl, cyano, cyanomethyl,##STR37## 2- or 4-pyridinyl or 2-pyrimidinyl, R is ashereinabovedefined, with the proviso that R is not hydrogen, and X, m, nand p are as hereinbeforedefined, a 1-unsubstituted 1H-indazole 8wherein R is as hereinbefore defined, with the proviso that R is nothydrogen, and X, m, n and p are as hereinbeforedefined, is treated,respectively, with an alkyl, alkenyl, cycloalkylalkyl,dialkylaminoalkyl, loweralkylcarbonyl halide, cyanogen, cyanomethyl, 2-or 4-pyridinyl or 2-pyrimidinyl halide, i.e., an iodide, bromide orchloride, or a compound of the formula ##STR38## wherein X", n", q' andp" are as defined above and Hal is iodo, bromo or chloro, in thepresence of an alkali metal hydride suspended in a polar aproticsolvent. Among alkali metal hydrides, there may be mentioned lithiumhydride, potassium hydride and sodium hydride. Sodium hydride ispreferred. Among polar aprotic solvents, there may be mentioneddimethylformamide, dimethylacetamide and hexamethylphosphoramide.Dimethylformamide is preferred. While the alkylation normally proceedsreadily at ambient temperature, the reaction may be conducted at anelevated temperature of about 50° to about 100° C. to facilitate theconversion. See Reaction Scheme C.

Alternatively, 1H-indazoles substituted at the 1-position by a group ofthe formula ##STR39## i.e., compounds of the formula 11 wherein R¹ is##STR40## wherein X" is hydrogen, halogen, alkyl, alkoxy, hydroxy oramino and p" is 1 or 2, may be prepared from the corresponding compoundswherein X" is nitro by conventional methods involving, for example,reduction of nitro group to an amino function, diazotization andsubsequent displacement or reduction of the diazonium moiety.

To provide a 1-hydroxymethyl-3-(piperidinyl)-1H-indazole 13 or1-hydroxymethyl-3-(pyrrolidinyl)-1H-indazole 13, a 1-unsubstituted3-(piperidinyl)-1H-indazole 8 or 1-unsubstituted3-(pyrrolidinyl)-1H-indazole 8 wherein R is as hereinbeforedefined, withthe exception that R is not hydrogen, is treated with formaldehyde inthe form of paraformaldehyde or trioxane in an alkanol such as methanol,ethanol, 2-propanol and the like, preferably ethanol, in the presence ofan alkali metal hydroxide such as lithium hydroxide, sodium hydroxide,or potassium hydroxide, sodium hydroxide being preferred, at an elevatedtemperature of about the reflux temperature of the reaction mixture.

To prepare the hydroxymethyl-1H-indazole 13 wherein R is hydrogen, oneconducts the condensation on, for example, anN-phenoxycarbonyl-1H-indazole of formula 10 and then removes thecarbamoyl group under conventional mild hydrolysis conditions.

To fabricate the 3-(piperidinyl)- or 3-(pyrrolidinyl)-1H-indazole systemof formula 1 wherein R is ##STR41## alkanoyl, formyl, R² OCO, ##STR42##or diloweralkylphosphinylmethyl, wherein R², X', p' and q are as definedabove, a 3-(piperidinyl)- or 3-(pyrrolidinyl)-1H-indazole of formula 18,i.e., a compound wherein the nitrogen atom of the 3-(piperidinyl) or3-(pyrrolidinyl) groups and the nitrogen atom occupying the 1-positionof the indazole system are unsubstituted, is treated with an alkanoyl orformyl halide, i.e., an alkanoyl or formyl iodide, bromide or chloride,or halide of the formulas ##STR43## wherein R², X', p' and q are asabove and Hal is iodo, bromo or chloro, in a halocarbon such asdichloromethane or trichloromethane, or a polar aprotic solvent, such asdimethylformamide, dimethylacetamide or hexamethylphosphoramide, in thepresence of an acid scavenger, such as sodium or potassium carbonate orsodium or potassium bicarbonate, to provide a 3-(piperidinyl)- or3-(pyrrolidinyl)-1H-indazole of formula 19 wherein R, X m, n and p areas above. Trichloromethane and dimethylformamide are the preferredsolvents, and potassium bicarbonate is the preferred scavenger.

To minimize formation of disubstituted products, i.e., compounds offormula 20 wherein R, X, m, n and p are as above, one generally performsthe acylation reaction, i.e., the conversion of 18 to 19, at aboutambient temperature, at which temperature only minor amounts of theN,N'-disubstituted product 20 are usually formed. The N-substituted andN,N'-disubstituted products 19 and 20 may be separated by conventionaltechniques such as recrystallization. In the event substantial amountsof the N,N'-disubstituted product are formed, or the separation provesto be difficult, one may transform the N,N'-disubstituted compound 20 toto the monosubstituted product 19 by alcoholysis. The alcoholysis isconveniently accomplished by means of an alkali metal alkoxide in analkanol. Suitable alkali metal alkoxides include lithium, sodium orpotassium methoxide, ethoxide, 1-propoxide and the like. Suitablealkanols include methanol, ethanol, 1-propanol and the like. Sodiummethoxide in methanol is preferred.

To provide the 1H-indazole 10 wherein R is hydrogen and X, m, n and pare as defined above an N-unsubstituted benzoylpiperidine 7 orN-unsubstituted benzoylpyrrolidine 7 is cyclized with hydrazine hydrateby the hereinbeforedescribed process.

Alternatively, to provide the 1H indazole 10 wherein R is hydrogen andX, m, n and p are as defined above, compound 19 where R is loweralkanoylor lower alkoxycarbonyl is subjected to hydrolysis at 50° to 150° C. for3 to 16 hours in the presence of aqueous alkanol e.g. C₂ H₅ OH, HO(CH₂)₂OH, etc.

3-(Piperidinyl)- or 3-(pyrrolidinyl)-1H-indazol systems of formula 1wherein R is cyano are also prepared by treating a 1-substituted1H-indazole of the formula 11 wherein R is alkyl and R¹ is formyl,alkanoyl or ##STR44## wherein X", p" and q' are as above with cyanogenbromide or chloride as hereinafterdescribed. For example, treatment of asolution of 1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazole (11 whereinR is methyl, R₁ is benzoyl, X is hydrogen, m and n are 2 and p is 1) andchloroform with cyanogen bromide in the presence of potassium carbonateprovides 4-(1-benzoyl-1H-indazol-3-yl) piperidine-1-carbonitrile (1wherein R is cyano, R¹ is benzoyl, X is hydrogen, m and n are 2 and p is1).

To prepare 1-substituted 1H-indazoles of formula 1 wherein R¹ is formyl,alkanoyl, cycloalkylalkanoyl ##STR45## R^(2') OCO or R⁵ CO whereinR^(2'), R⁵, X", p" and q' are as above, a 1-unsubstituted 1H-indazole 8wherein R is as above, with the proviso that R is not hydrogen, and X,m, n and p are as before, is treated, respectively, with a formyl,alkanoyl or cycloalkylalkanoyl chloride, bromide or iodine, a compoundof the formula ##STR46## R^(2') OCOHal or R⁵ COHal wherein R^(2'), R⁵,X", p" and q' are as above and Hal is iodo, bromo or chloro, or thecorresponding acid anhydrides thereof, at an elevated temperature ofabout the reflux temperature of the reaction medium. For example,treatment of a 1H-indazole 8 wherein R is methyl with acetic anhydrideat the reflux temperature of the reaction mixture affords a1-acetyl-1H-indazole 14 wherein R² is methyl, and treatment of a1H-indazole 8 wherein R is methyl with benzoyl chloride at a reactiontemperature of about 100° C. yields a 1-benzoyl-1H-indazole 14 whereinR² is phenyl.

Alternatively, the synthesis of 1-substituted 1H-indazoles of formula 1wherein R¹ is formyl, alkanoyl, cycloalkylalkanoyl, ##STR47## R² OCO orR⁵ CO, wherein R², R⁵, X', p' and q are as above, is accomplished bycontacting a formyl, cycloalkylalkanoyl or alkanoyl halide or compoundof the formula ##STR48## R^(2') OCOHal or R⁵ COHal wherein R^(2'), X",p" and q' are as above, with a 1-unsubstituted-1H-indazole 8 in ahalocarbon such as dichloromethane or trichloromethane, preferablytrichloromethane, in the presence of an acid scavenger such as sodium orpotassium carbonate, or sodium or potassium bicarbonate, preferablypotassium carbonate. The reaction proceeds readily at moderatetemperatures. To promote the conversion however, elevated temperatures,i.e., the reflux temperature of the reaction medium are, generallyemployed.

To provide 1-substituted 1H-indazoles 11, wherein R¹ is ##STR49##wherein X" and p" are as described hereinbefore, a 1-unsubstituted1H-indazole 8 is treated with a benzenesulfonyl halide of the formula##STR50## wherein X" and p" are as described hereinbefore and Hal ischloride or bromide at an elevated temperature within the range of about80° to about 150° C., a reaction temperature of about 100° C. beingpreferred.

1H-indazoles of the formula 11 wherein R¹, X, m, n and p are as aboveand R is hydrogen are prepared from 1H-indazoles of formula 11 whereinR¹, X, m, n and p are as above and R is alkyl by the conversion of a3-(1-alkylpiperidinyl)- or 3-(1-alkylpyrrolidinyl)-1H-indazole 11wherein R is alkyl and R¹, X, m, n and p are as above to a3-(1-cyanopiperidinyl)- or 3-(1-cyanopyrrolidinyl)-1H-indazole 11,wherein R is cyano and R¹, X, m, n and p are as above, followed byremoval of the cyano group to a 1H-indazole of formula 11 wherein R ishydrogen and R¹, X, m, n and p are as above. The conversion of a1-alkylpiperidine 11 or 1-alkylpyrrolidine 11 wherein R is alkyl to thecorresponding 1-cyano compound 11 wherein R is cyano is accomplished bytreating the alkylpiperidine 11 or alkylpyrrolidine 11 with a cyanogenhalide such as cyanogen bromide or chloride in the presence of a acidacceptor such as sodium or potassium carbonate or sodium or potassiumbicarbonate in a suitable solvent. Suitable solvents include halocarbonssuch as dichloromethane, trichloromethane, 1,2-dichloroethane and thelike, and dipolar aprotic solvents such as dimethylformamide,dimethylacetamide, hexamethylphosphoramide, and dimethylsulfoxide.Cyanogen bromide is the preferred halide and dimethylsulfoxidecontaining potassium carbonate is the preferred reaction medium. Theconversion temperature is not critical. To avoid side-reactions,however, it is preferred to perform the reaction at reduced temperaturesbetween about 0° and about 30° C. A temperature of about 25° C. ispreferred.

The removal of the cyano group of compounds of formula 11 wherein R iscyano may be effected directly under conventional hydrolytic conditions,utilizing for example, aqueous organic acids such as aqueous aceticacid, or mineral acids such as dilute hydrochloric acid or sulfuricacid.

1H-Indazoles of the formula 11 wherein R¹, X, m, n and p are as above,with the proviso that R₁ is not hydrogen, and R is formyl are preparedfrom 1H-indazoles of formula 11 wherein R¹, X, m, n and p are as above,with the proviso that R¹ is not hydrogen, by reaction thereof withformic acid in the presence of a mixture of formic acid and aceticanhydride at a temperature of 50° to 100° C. for 1 to 16 hours in thepresence of the ethereal solvent. The presence of the ethereal solventis not necessary, however.

N-Unsubstituted 1H-indazoles, i.e., 1H-indazoles of formula 18 whereinboth the indazole and piperidine (or pyrrolidine) nitrogen atoms areunsubstituted, are prepared by an alternative synthesis involving thecondensation of an appropriately substituted fluorobenzene of formula 15wherein X and p are selected from the groups described above with anN-formyl- or N-alkanoyl-(piperidinyl)- or (pyrrolidinyl)carbonyl halideof formula 16 wherein R is formyl or alkanoyl and Hal is chloro orbromo, followed by cyclization of the resulting(2-fluorobenzoyl)piperidine 17 or (2-fluorobenzoyl)pyrrolidine 17 to the1H-indazole 18.

To provide aN-loweralkyl-N'-hydroxyloweralkyl-3-(piperidinyl)-1H-indazole 11 or aN-loweralkyl-N'-hydroxyloweralkyl-3-(pyrrolidinyl)-1H-indazole 11, i.e.,a compound of formula 11 wherein R is loweralkyl and R¹ ishydroxyloweralkyl, aN-loweralkyl-N'-loweralkoxycarbonylloweralkyl-3-(piperidinyl)-1H-indazole11 or aN-loweralkyl-N'-loweralkoxycarbonylloweralkyl-3-(pyrrolidinyl)-1H-indazole11, i.e., a compound of formula 11 wherein R is loweralkyl and R¹ isloweralkoxycarbonylloweralkyl, is reduced with an alkali metal aluminumhydride such as, for example, lithium aluminum hydride, in an etherealsolvent such as for example, tetrahydrofuran, at the reflux temperatureof the reaction mixture.

To provide a N'-hydroxylowerlakyl-3-(piperidinyl)-1H-indazole 11 or aN'-hydroxyloweralkyl-3-(pyrrolidinyl)-1H-indazole 11, i.e., a compoundwherein R¹ is hydroxyloweralkyl and R is a group as hereinbeforedefinedother than loweralkyl, aN-loweralkyl-N'-hydroxyloweralkyl-3-(piperidinyl)-1H-indazole 11 or aN-loweralkyl-N'-hydroxyloweralkyl-3-(pyrrolidinyl)-1H-indazole 11, i.e.,a compound wherein R is other than loweralkyl and R¹ ishydroxyloweralkyl is transformed by the processes ashereinbeforedescribed, involving the removal of the loweralkyl groupand, for example, alkylation or acylation of the N-unsubstitutedcompound, so obtained.

The condensation of fluorobenzene 15 with a carbonyl halide 16 isaccomplished under Friedel-Crafts conditions as described in U.S. Pat.No. 4,355,037, granted Oct. 19, 1982.

The cyclization of a (2-fluorobenzoyl)piperidine 17 or(2-fluorobenzoyl)pyrrolidine 17 to a 1H-indazole 18 is performed withhydrazine hydrate in an alkanol at an elevated temperature, conditionsunder which the N-formyl or N-alkanoyl group of the piperidine orpyrrolidine ring is removed. Suitable alkanols include ethanol,2-propanol, 1-butanol, 3-pentanol and the like. 1-Butanol is preferred.A cyclization temperature of the boiling point of the reaction medium isalso preferred.

To preserve the N-acyl group of the piperidine or pyrrolidine ring, onemay cyclize the hydrazone of a (2-fluorobenzoyl)piperidine 17 or(2-fluorobenzoyl)pyrrolidine 17, prepared by methods well-known in theart, by means of an alkali metal hydride, for example, sodium hydride,in a dipolar aprotic solvent, for example, diemthylformamide, at anelevated temperature of about 80°-120° C.

1 H-Indazoles substituted at the 1-position by a loweralkyl group, i.e.,compounds of formula 1 wherein R¹ is loweralkyl, are also prepared byreducing a 1-loweralkanoyl- or 1-loweralkoxycarbonyl-3-(piperidinyl)- or3-(pyrrolidinyl)-1H-indazole of formula 19, the synthesis of which ishereinbeforedescribed, by an alkali metal aluminum hydride such as forexample, lithium aluminum hydride, in an ethereal solvent such astetrahydrofuran, at the reflux temperature of the reaction medium.

1H-Indazoles of formula 11 wherein R¹, X, m, n, and p are as above and Ris ##STR51## where R⁶ is as previously defined, are prepared from1H-indazoles of formula 11 wherein R¹, X, m, n and p are as above and Ris cyano, or from 1-substituted 1H-indazoles of formula 14 where R², m,n, and p are as above and R is cyano, by reaction with an alcohol of theformula R⁶ OH, typically in the presence of an alkali metal cyanide suchas potassium cyanide. Ordinarily the reaction is conducted in thepresence of alkali metal cyanide such as potassium cyanide and an excessamount of the alcohol R⁶ OH, which also works as a reaction medium. Atypical reaction condition is refluxing the reaction mixture for severalhours and then further continuing the reaction at ambient temperaturefor 10-20 hours. In an alternative procedure, the 1H-indazole, above,where R is cyano, is reacted with an alcohol of the formula R⁶ OH in thepresence of (usually only catalytic amount) of an alkali metal alkoxideof formula MOR⁶ where M is an alkali metal, preferably sodium. Usuallysodium metal is added to an excess amount of an alcohol of formula R⁶ OHto form the sodium alkoxide of formula NaOR⁶. Thereafter the cyanosubstituted 1H-indazole 11 is added to the mixture and if necessary themixture is heated slightly until a uniform solution is formed.

1H-Indazoles of formula 11 wherein R¹, X, m, n, and p are as above and Ris ##STR52## where R⁷ is other than hydrogen, are prepared from1H-indazoles of formula 11 wherein R¹, X, m, n, and p are as above and Ris hydrogen or from compounds 14 above, R, m, n, and p are as above andR is hydrogen by reaction with an isocyanate or isothiocyanate of theformula R⁷ --N═C═Y (Y is oxygen or sulfur) to afford a urea derivative##STR53## This reaction is typically conducted in a suitable medium suchas benzene or toluene at a temperature between room temperature and thereflux temperature, for example by refluxing the reaction mixture for1-24 hours. Suitable reagents are, for example, methylisothiocyanate,methylisocyanate, phenylisocyanate and other isothiocyanates orisocyanates. Compound 21 is then halogenated, e.g. chlorinated by theuse of an inorganic halide, e.g. SOCl₂, PCl₃, etc. to form compound 22##STR54## This reaction, e.g., chlorination, is typically conducted byrefluxing a mixture comprising compound 21, the inorganic halide, e.g.PCl₅, and a suitable medium such as chlorobenzene until the evolution ofthe hydrogen halide, e.g. hydrogen chloride, ceases. Finally compound 22is reacted with an equivalent amount of an alkali metal alkoxide of analcohol R⁶ OH to afford compound 11 where R is ##STR55## where R⁷ is asdefined above and is other than hydrogen. This reaction is typicallyconducted in either the alcohol R⁶ OH as a solvent or in an inertsolvent such as toluene or dimethylformamide (DMF) at reflux temperature(in the case of R⁶ OH or toluene, for instance) or an elevatedtemperature (in the case of DMF, for instance) for a suitable length oftime such as for example 0.5 to 24 hours.

1H-Indazoles of formula 11 wherein R¹, X, m, n and p are as above and Ris ##STR56## are prepared from 1H-indazoles of formula 11 wherein R¹, X,m, n and p are as above and R is cyano, by hydrolysis thereof. This is aconventional hydrolysis of a nitrile group and is typically conducted inthe presence of base, e.g. NaOH, or acid e.g. H₂ SO₄ (dilute). Thecompounds are also available from 1H-indazoles of the formula 11 whereinR', X, m, n, and p are as defined above and R is hydrogen by reactingthem with nitrourea preferably in a polar solvent as, for example,ethanol or acetone, preferably at a temperature between room temperatureand the refluxing temperature of the reaction mixture.

1H-Indazoles of the formula 11 wherein R', X, m, n and p are as definedabove and R is ##STR57## (Y, R⁸ and R⁹ are as defined above, however R⁸═R⁹ ═ hydrogen) are prepared from 1H-indazoles, of the formula 11wherein R', X, m, n and p are as defined above and R is hydrogen byreacting them with a halogenide of the formula ##STR58## wherein R⁸, R⁹and Y are as defined above and Hal denotes halogen, preferably chlorine.This reaction is typically conducted in a suitable medium such asbenzene or toluene at a temperature between room temperature andrefluxing temperature preferably in the presence of a base such as atrialkylamine.

In an alternative procedure, referring to Reaction Schemes A and B, C &D, the 1-alkyl-(2-fluorobenzoyl)piperidine 5, or -pyrrolidine 5, the1-phenoxycarbonyl-(2-fluorobenzoyl)piperidine or -pyrrolidine 6, the(2-fluorobenzoyl)-piperidine or -pyrrolidine 7, the N-substitutedbenzoyl piperidine or -pyrrolidine 9 or the (2-fluorobenzoyl)piperidineor -pyrrolidine 17 are reacted with a substituted hydrazine of theformula H₂ N-NHR¹ to form a compound of the formula ##STR59## Thereaction is typically carried out at 40° to 110° C. for 2 to 16 hours inthe presence of an alkanoic solvent, e.g. ethanol, isopropanol, etc. Theresultant compound 21a is then cyclized by treatment with a strong base,such as NaH, KO-t-C₄ H₉, NaNH₂, etc. at a temperature of 25° to 120° C.for 3 to 16 hours in the presence of an aprotic solvent, e.g. DMF, THF,etc. to form compound of the formula ##STR60##

1H-Indazoles of the formula 11 wherein R¹, X, m, n and p are as definedabove and R is ##STR61## where R⁶ is as defined above, and R⁷ ishydrogen, are prepared from 1H-indazoles of the formula 11, wherein R iscyano, by reacting them with an alcoholate of the formula MOR⁶, where Mis a metal, e.g. NaOR⁶. This reaction is typically conducted at atemperature of 25° to 100° C., for 1 to 16 hours, in an alkanoic (R⁶ OH)solvent, e.g. methanol, ethanol, etc. In addition, the resultantcompounds where R is --C--OR⁶ can be converted to compounds 11 where Ris ##STR62## by reaction thereof with an acid, e.g. HBr, at 50° to 90°C. for 3 to 16 hours.

1H-Indazoles of the formula 11 wherein R¹, X, m, n and p are as aboveand R is ##STR63## where R⁹ is as previously defined, are prepared from1H-indazoles of the formula 11 wherein R¹, X, m, n and p are as aboveand R is hydrogen, by reaction thereof with an isocyanate orisothiocyanate of the formula R9--N═C═Y where R9 and Y are as previouslydefined. The reaction is typically carried out at a temperature of 25°to 110° C. for 1 to 16 hours in a hydrocarbon solvent, e.g. benzene,toluene, etc.

1H-Indazoles of the formula 11 wherein R', X, m, n and p are as aboveand R is ##STR64## are prepared from 1H-Indazoles of formula 11 whereinR', X, m, n and p are as above and R is hydrogen by reaction thereofwith nitrourea at a temperature of 25° to 100° C. for 1 to 16 hours in apolar solvent e.g. ethanol, DMF, etc.

The synthesis of 3-(3-haloalkyl)-6-fluoro-1,2-benzisoxazoles,4,4-bis(4-fluorophenyl)butyl halides, 3-(phenylsulfonylalkyl)indoles and3-(alkylphenylsulfonylalkyl)indoles,1-(3-haloalkyl)1,2-dihydro-2H-benzimidazol-2-ones; and4-fluorobenzoylalkyl halides ethylene glycol ketals requisite precursorsfor the preparation of 3-(4-piperidinyl)-1H-indazoles and3-(3-pyrrolidinyl)-1H-indazoles of the present invention, substituted atthe indazole and/or piperidine or pyrrolidine nitrogen atoms, aredescribed in U.S. Pat. No. 4,352,811, granted Oct. 5, 1982.

The 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of the presentinvention are useful for treating psychoses by virtue of their abilityto elicit an antipsychotic response in mammals.

Antipsychotic activity is determined in the climbing mice assay bymethods similar to those described by P. Protais, et al.,Psychopharmacol., 50, 1 (1976) and B Costal, Eur. J. Pharmacol., 50, 39(1978).

The subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×4" by 10") and are allowed one hour for adaptation andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally (i.p.) 30 minutes prior to the apomorphinechallenge at a screening dose of 10 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20, and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior     Score                                                   ______________________________________                                        Mice with:                                                                    4 paws on bottom (no climbing)                                                                      0                                                       2 paws on the wall (rearing)                                                                        1                                                       4 paws on the wall (full climb)                                                                     2                                                       ______________________________________                                    

Mice consistently climbing before the injection of apomorphine will bediscarded.

With full-developed apomorphine climbing, the animals are hanging ontothe cage walls, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits, calculated by a Linear RegressionAnalysis of some of the instant 3-(piperidinyl)-1H-indazoles and3-(pyrrolidinyl)-1H-indazoles as well as standard antipsychotics, arepresented in Table 1.

                  TABLE 1                                                         ______________________________________                                                           ANTIPSYCHOTIC                                                                 ACTIVITY                                                   COMPOUND           ED.sub.50 mg/kg, i.p.)                                     ______________________________________                                        3-(1-methyl-4-piperidinyl)-1H--                                                                  4.5                                                        indazole                                                                      3-(1-methyl-4-piperidinyl)-1-                                                                    46% @ 10 mg/kg*                                            trichloroethoxycarbonyl-1H--                                                  indazole                                                                      1-ethyl-3-(1-methyl-4-                                                                           41% @ 10 mg/kg*                                            piperidinyl)-1H--indazole                                                     1-acetyl-3-(1-methyl-4-                                                                          5.4                                                        piperidinyl)-1H--indazole                                                     1-benzoyl-3-(1-methyl-4-                                                                         6.5                                                        piperidinyl)-1H--indazole                                                     1-benzoyl-6-fluoro-3-(1-methyl-                                                                  1.8                                                        4-piperidinyl)-1H--indazole                                                   3-(1-[4,4-bis(4-fluorophenyl)-                                                                   7.4                                                        butyl]-4-piperidinyl)-1H--                                                    indazole                                                                      1-cyclopropylmethyl-3-                                                                           36% @ 10 mg/kg*                                            (1-methyl-4-piperidinyl)-1H--                                                 indazole                                                                      haloperidol (standard)                                                                           0.11                                                       sulpiride (standard)                                                                             14.5                                                       ______________________________________                                         *% decrease in climbing score at indicated dose, i.p.                    

Antipsychotic response is achieved when the present 3-(piperidinyl)- and3-(pyrrolidinyl)-1H-indazoles are administered to a subject requiringsuch treatment at an effective oral, parenteral or intravenous dose offrom 0.01 to 50 mg/kg of body weight per day. A particularly preferredeffective amount is about 25 mg/kg of body eight per day. It is to beunderstood, however, that for any particular subject, specific dosageregimens should be adjusted according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the aforesaid compound. It is to be further understoodthat the dosages set forth herein are exemplary only and they do not, toany extent, limit the scope of practice of the invention.

The 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of the presentinvention are useful as analgetics due to their ability to alleviatepain in mammals. The analgetic utility is demonstrated in thephenyl-p-quinone writhing assay in mice, a standard assay for analgesia[Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)]. Thus, for instance, thesubcutaneous (s.c.) dose effecting an approximately 50% inhibition ofwrithing (ED₅₀) in mice produced in this assay is as follows:

    ______________________________________                                                           ED.sub.50                                                  COMPOUND           mg/kg, s.c.                                                ______________________________________                                        3-(1-methyl-4-piperidinyl)-                                                                      0.26                                                       1H--indazole                                                                  1-ethyl-3-(1-methyl-4-                                                                           0.65                                                       piperidinyl)-1H--indazole                                                     1-acetyl-3-(1-methyl-4-                                                                          0.71                                                       piperidinyl)-1H--indazole                                                     1-benzoyl-3-(1-methyl-4-                                                                         0.85                                                       piperidinyl)-1H--indazole                                                     1-phenylmethyl-3-(1-methyl-                                                                      75% @ 20 mg/kg*                                            4-piperidinyl)-1H--indazole                                                                      96% @ 20 mg/kg*                                            3-[1-[4,4-bis(4-fluorophenyl)-                                                                   31% @ 20 mg/kg*                                            1-butyl]-4-piperidinyl]-1H--                                                  indazole                                                                      1-cyclopropylmethyl-3-(1-                                                                        1.1                                                        methyl-4-piperidinyl)-1H--                                                    indazole                                                                      1-[3-(dimethylamino)propyl]-                                                                     15% @ 20 mg/kg*                                            3-(1-methyl-4-piperidinyl)-1H--                                               indazole                                                                      1-[4-(trifluoromethyl)phenyl]-                                                                   9.8                                                        3-(1-methyl-4-piperidinyl)-1H--                                               indazole                                                                      1-benzoyl-6-fluoro-3-(1-methyl-                                                                  0.17                                                       4-piperidinyl)-1H--indazole                                                   propoxyphene (standard)                                                                          3.9                                                        pentazocine (standard)                                                                           1.3                                                        ______________________________________                                         *inhibition of writhing at indicated dose, s.c.                          

Analgesia production is achieved when the present 3-(piperidinyl)- and3-pyrrolidinyl)-1H-indazoles are administered to a subject requiringsuch treatment as an effective oral, parenteral or intravenous dose offrom 0.01 to 100 mg/kg of body weight per day. A particularly effectiveamount is about 5 mg/kg of body weight per day. It is to be understood,however, that for any particular subject, specific dosage regimensshould be adjusted according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the aforesaid compound. It is to be further understood that thedosages set forth herein are exemplary only and that they do not, to anyextent, limit the scope or practice of the invention.

The 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of the presentinvention are also useful as antidepressants by virtue of their abilityto elicit an antidepressant response in mammals. The antidepressantactivity is demonstrated in the tetrabenazine induced ptosis assay inmice [International Journal of Neuropharmacology, 8, 72 (1969)], astandard assay for antidepressant activity. Thus, for example, theintraperitoneal (i.p.) dose effecting an estimated 50% inhibition ofptosis (ED₅₀) in mice produced in this assay is as follows:

    ______________________________________                                                           ED.sub.50                                                  COMPOUND           (mg/kg, i.p.)                                              ______________________________________                                        1-(2-chlorophenyl)-3-                                                                            5.3                                                        (1-methyl-4-piperidinyl)-                                                     1H--indazole                                                                  1-(2-chlorophenyl)-3-                                                                            5.9                                                        (4-piperidinyl)-1H--                                                          indazole                                                                      1-(2-aminophenyl)-3-                                                                             19.2                                                       (1-methyl-4-piperidinyl)-                                                     1H--indazole                                                                  1-(2-fluorophenyl)-3-                                                                            1.7                                                        (1-methyl-4-piperidinyl)-                                                     1H--indazole                                                                  1-(3-fluorophenyl)-3-                                                                            5.0                                                        (1-methyl-4-piperidinyl)-                                                     1H--indazole                                                                  6-fluoro-1-(2-fluoro-                                                                            6.3                                                        phenyl)-3-(1-methyl-4-                                                        piperidinyl)-1H--indazole                                                     imipramine (standard)                                                                            1.3                                                        amitriptyline (standard)                                                                         1.5                                                        ______________________________________                                    

Antidepressant response is achieved when the present 3-(piperidinyl)-and 3-(pyrrolidinyl)-1H-indazoles are administered to a subjectrequiring such treatment as an effective oral, parenteral or intravenousdose of from 0.01 to 50 mg/kg of body weight per day. A particularlypreferred effective amount is about 10 mg/kg of body weight per day. Itis to be understood, however, that for any particular subject, specificdosage regimens should be adjusted according to the individual need andthe professional judgment of the person administering or supervising theadministration of the aforesaid compound. It is to be further understoodthat the dosages set forth herein are exemplary only and they do not, toany extent, limit the scope or practice of the invention.

Compounds of the present invention include:

(a) 3-(3-pyrrolidinyl)-1H-indazole

(b) 3-(1-propenyl-4-piperidinyl)-1H-indazole

(c)3-(4-cyclopropylmethyl-3-piperidinyl)-6-methyl-1-(2-pyrimidinyl)-1H-indazole

(d) 3-[1-butyl-3-pyrrolidinyl]-4-methoxy-1-(2-pyridinyl)-1H-indazole

(e) 3-(1-cyanomethyl-3-piperidinyl)-7-trifluoromethyl-1H-indazole

(f) 1-(4-fluorobenzoyl)-3-(4-piperidinyl)-5-nitro-1H-indazole

(g)3-(1-acetyl-4-piperidinyl)-4-amino-1-(4-fluorobenzoylethyl)-1H-indazole

(h) 3-[1-(1-methylindol-3-propyl)-3-piperidinyl]-1H-indazole

(i) 1-formyl-3-(1-formyl-4-piperidinyl)-1H-indazole

(j)5,6-dichloro-3-[1-(4-(fluorobenzoylpropyl)-4-piperidinyl]-1-(propen-1H-indazole

(k) 1-cyano-3-[1-(4-fluorobenzoylpropyl)-3-pyrrolindinyl]-1H-indazoleethylene ketal

(l)1-cyanomethyl-3-[1-(6-fluoro-1,2-benzisoxazol-3-propyl)-3-piperidinyl]-1H-indazole

(m) 3-(1-phenoxycarbonyl-4-piperidinyl)-1-(4-picolinoyl)-1H-indazole

(n)3-[1-[1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-ylpropyl]-4-piperidinyl]-1-(2-thiazolylcarbonyl)-1H-indazole

(o) 3-[1-(3-phenylpropyl)-4-piperidinyl]-1H-indazole

(p) 3-[1-(1-methylindol-3-propyl)-3-piperidinyl]-1H-indazole

The compounds of the invention are also useful as antihypertensiveagents due to their ability to depress blood pressure in mammals.Antihypertensive activity is measured in the spontaneous hypertensiverat by the indirect tail cuff method described in "Methods inPharmacology," A. Schwartz, Ed., Vol. I, Appleton-Century Crofts, NewYork, 1971, p. 135. In this procedure a group of five animals aretreated orally (p.o.) for three days with the test compound in relationto the control group of the same number. The drop in blood pressure ismeasured on the third day following administration. The antihypertensiveactivities of some of the compounds, expressed as mm decrease in meanarterial blood pressure are given below:

    ______________________________________                                                                       Decrease in                                                      Dose (mg/kg p.o.                                                                           Blood                                                            of body weight,                                                                            Pressure                                       Compound          parenteral)  (mm Hg)                                        ______________________________________                                        4-(1H--indazol-3-yl)piperidine-1-                                                                3           47                                             carboximidic acid methyl                                                      ester                                                                         4-(6-fluoro-1H--indazol-3-yl)-                                                                  30           88                                             piperidine-1-carboximidic                                                     acid methyl ester                                                             guanethidine      50           20                                             ______________________________________                                    

Blood pressure reduction is achieved when the compounds of the inventionare administered to a subject requiring such treatment at an effectiveoral, parenteral or intravenous doses of from 0.1 to 50 mg/kg of bodyweight per day. A preferred effective dose within this range is fromabout 0.1 to 5 mg/kg of body weight per day. A particularly preferredeffective amount is about 10 mg/kg of body weight per day. It is to beunderstood, however, that for any particular subject, specific dosageregimens should be adjusted according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compounds of the invention. It is to be furtherunderstood that the dosages set forth herein are examples only and thatthey do not, to any extent, limit the scope or practice of theinvention.

The compounds of the invention are also useful as anticonvulsants due totheir anticonvulsant activity in mammals. Anticonvulsant activity ismeasured in the male mouse using the supramaximal electroshock (SES)assay described in Arch. Int. Pharmacodyn. 92: 97-107, 1952. In thisprocedure groups of animals are used. Drugs are prepared using distilledwater and, if insoluble, a surfactant is added. Control animals receivevehicle. Drugs are routinely administered intraperitoneally (i.p). Thedosage volume is 10 ml/kg. A primary screen is given a 30 minutepretreat. The animal's eyes are placed across the output terminals of anA.C. shocker that delivers 206 volts rms for 300 msec. Electrode pastecoats the animals eyes at the point of contact with the terminals. Acompound is considered to give protection if the mouse does not exhibitextensor tonus. Protection is expressed as normalized percent inhibitionrelative to vehicle control.

A time response is carried out using six animals/group. Animals aretested at 30, 60 and 120 minutes postdrug. Additional time periods aretested if indicated by previous tests. When the peak activity time hasbeen determined, a dose response is initiated using 10 animals/group atthat time period. The ED₅₀ and 95% confidence interval are calculated bycomputer probit analysis.

Anticonvulsant activity is also measured using the metrazol lethality(MTZ). In this procedure groups of male mice are utilized. Test drugsare prepared using distilled water and, if insoluble, a suitablesurfactant is added. The route of administration is i.p., but alladministrations are in volumes proportional to 10 cc/kg.

For a time response, 25 animals (5/group) are administered drug i.p. at15, 30, 60 and 90 minutes prior to Metrazol treatment. Control animals(2/group) receive vehicle. Metrazol (pentylenetetrazol) is prepared at aconcentration of 225 mg/10 ml in distilled water. Metrazol isadministered s.c. at 225 mg/kg in distilled water. Those animals alive15 minutes after Metrazol injection are considered protected. The timeperiod with the gretest percent protected is said to be that of peakdrug activity.

A dose range is run in the same manner as a time response except that 50animals (10/group) are tested at the peak time of drug activity. Onegroup receives vehicle. An ED₅₀ is calculated by means of linearregression.

The anticonvulsant activities of some of the compounds are given below:

    __________________________________________________________________________     ##STR65##                                                                    Compound                    (ED.sub.50 mg/kg i.p.)                            No.   X    R'        R      MTZ   SES                                         __________________________________________________________________________    1     H                                                                                   ##STR66##                                                                              CONHCH.sub.3                                                                         49    37                                          2     6-fluoro                                                                            ##STR67##                                                                              CONHC.sub.6 H.sub.5                                                                  20% @ 60                                                                             0% @ 60                                    3     H                                                                                   ##STR68##                                                                              CONH.sub.2.HBr                                                                       27.4  10.9                                        4     6-fluoro                                                                            ##STR69##                                                                              CONHCH.sub.3                                                                          0% @ 60                                                                            64.9                                        5     6-fluoro                                                                            ##STR70##                                                                              CSNHC.sub.6 H.sub.5                                                                  17% @ 60                                                                             0% @ 60                                    6     H                                                                                   ##STR71##                                                                              CONHCH.sub.3                                                                         20% @ 60                                                                            44.9                                        7     H                                                                                   ##STR72##                                                                              COCH.sub.3                                                                           60% @ 60                                                                             0% @  60                                   8     6-Br                                                                                ##STR73##                                                                              COCH.sub.3                                                                            0% @ 60                                                                            33% @ 60                                    9     H                                                                                   ##STR74##                                                                              CONHCH.sub.3                                                                         45.5  31.7                                        10    H                                                                                   ##STR75##                                                                              COCH.sub.3                                                                           45.5  35.3                                        11    H                                                                                   ##STR76##                                                                              CONH.sub.2                                                                           79.6  33.7                                        12    H                                                                                   ##STR77##                                                                              CHO    60.9  27.2                                        13    H                                                                                   ##STR78##                                                                              CHO    40% @ 60                                                                            24.7                                        14    6-fluoro                                                                            ##STR79##                                                                              CONH.sub.2                                                                           39.9  34.9                                        15    6-chloro                                                                            ##STR80##                                                                              CONH.sub.2                                                                           31.2  48.1                                        16    H                                                                                   ##STR81##                                                                              CON(CH.sub.3).sub.2                                                                  20%  @ 60                                                                           20% @ 60                                    __________________________________________________________________________

Anticonvulsant activity is achieved when the compounds of the invention,especially such compounds of the formula ##STR82## wherein R is formyl,loweralkanoyl, or ##STR83## R¹ is ##STR84## and p, p", X, X", Y, R⁸ andR⁹ are as defined above, are administered to a subject requiring suchtreatment at an effective oral, parenteral or intravenous dose of from0.1 to 100 mg/kg of body weight per day. A preferred effective dosewithin this range is from about 5 to 50 mg/kg of body weight per day. Aparticularly preferred effective amount is about 20 mg/kg of body weightper day. It is to be understood, however, that for any particularsubject, specific dosage regimens should be adjusted according to theindividual need and the professional judgement of the personadministering or supervising the administration of the compounds of theinvention. It is to be further understood that the dosages set forthherein are examples only and that they do not, to any extent, limit thescope or practice of the invention.

Effective amounts of the present invention may be administered to asubject by any one of various methods, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of thepresent invention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable additionsalts for purposes of stability, convenience or crystallization,increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofmineral acids, for example, hydrochloric acid, sulfuric acid, nitricacid and the like, salts of monobasic carboxylic acids such as, forexample, acetic acid, propionic acid and the like, salts of dibasiccarboxylic acids such as, for example, maleic acid, fumaric acid and thelike, and salts of tribasic carboxylic acids such as, for example,carboxysuccinic acid, citric acid and the like.

Effective quantities of the compounds of the invention may beadministered orally, for example, with an inert diluent or with anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theaforesaid compounds may be incorporated with excipients and used in theform of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gums and the like. These preparations should contain atleast 0.5% of active compound, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of active compound in such composition issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that anoral dosage unit form contains between 1.0-300 milligrams of the activecompound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragancanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin or a flavoring agent such as peppermint, methyl salicylate, ororange flavoring may be added. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 50% of the weightthereof. The amount of active compounds in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. ##STR85## wherein R, X, m,n and p are as hereinbefore described. ##STR86## wherein R, Y, m, n andp are as hereinbefore described. ##STR87## wherein R, R¹, R², X, m, nand p are as hereinbefore described. ##STR88## wherein R, R¹, X, Hal, m,n and p are as before. The parenteral preparation can be enclosed inampules, disposable syringes or multiple dose vials made of glass orplastic.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees centigrade (°C.).

EXAMPLE 1 4-(2-Fluorobenzoyl)-1-methylpiperidine hydrochloride

To a suspension of 7.6 g of magnesium turnings in 25 ml oftetrahydrofuran was added a few drops of ethyl bromide, with stirringunder nitrogen. After the reaction began approximately 50.0 g ofN-methyl-4-chloropiperidine in 125 ml of tetrahydrofuran was addeddropwise at a rate such that moderate reflux was maintained. Thereaction was heated under reflux for an additional hour. A solution of37.2 g of o-fluorobenzonitrile in 30 ml of tetrahydrofuran was addeddropwise. After completion of the addition the reaction mixture washeated under reflux for two hrs and stirred overnight at roomtemperature. The reaction mixture was poured into a solution of 85 g ofammonium chloride in 1200 ml of ice water and heated on a stream bathfor 3 hrs. The mixture was cooled, extracted with benzene (3x, 250 ml)and dried over anhydrous sodium sulfate. Removal of the solvent underreduced pressure gave an oil. A 1.0 g-portion of the oil was dissolvedin ether and a solution of ethereal hydrogen chloride was added. Theprecipitate was collected, dried and twice recrystallized fromethanol-ether to give 0.5 g (42%) of product, mp 167°-169° C.

Analysis: Calculated for C₁₃ H₁₇ ClFNO: 60.58% C, 6.65% H, 5.43% N,7.37% F. Found: 60.30% C, 6.78% H, 5.43% N, 7.59% F.

EXAMPLE 2 1-Phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine

To a solution of 57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine and68.7 g of potassium carbonate in 750 ml of toluene was added withstirring 47 g of phenylchloroformate. The reaction mixture was heatedunder reflux for 5 hrs, cooled to room temperature, filtered, and thesolvent removed under reduced pressure to give an oil. Trituration ofthe oil with hexane gave 48.6 g (46%) of product. Recrystallization of1.0 g of product from ethanol-water (2x) and from ethanol gave theanalytical sample, mp 95°-96° C.

Analysis: Calculated for C₁₉ H₁₈ FNO₃ : 69.71% C, 5.54% H, 4.28% N,5.81% F. Found: 69.45% C, 5.67% H, 4.13% N, 6.10% F.

EXAMPLE 3 4-(2-Fluorobenzoyl)piperidine hydrochloride

A solution of 40.5 g of 1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine,500 ml of ethanol and 500 ml of 30% of potassium hydroxide solution wasstirred at a temperature slightly below reflux overnight. The reactionmixture was cooled to room temperature, diluted with 250 ml of water,and the ethanol partially removed under reduced pressure. The aqueoussuspension was extracted with ether (2×150 ml) and the ether fractionsubsequently extracted with 1N hydrochloric acid (2×200 ml). The aqueoussolution was basified with 25% sodium hydroxide solution, extracted withether (2×150 ml) and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure to give an oil. The oil was dissolvedin a minimum amount of ethanol and a solution of ethereal hydrogenchloride was added dropwise until a precipitate formed. The solid wascollected and dried to give 9.7 g (40%) of product. Recrystallizationtwice from ethanol-ether gave the analytical sample, mp 185°-187° C.

Analysis: Calculated for C₁₂ H₁₅ ClFNO: 59.14% C, 6.20% H, 5.74 % N,7.80% F. Found: 58.90% C, 6.36% H, 5.50% N, 7.56% F.

EXAMPLE 4 3-(1-Methyl-4-piperidinyl)-1H-indazole

An autoclave was charged with 10.0 g of4-(2-fluorobenzoyl)-1-methylpiperidine and 14 ml of hydrazine hydrate.The reaction was heated at 150° for 20 hrs, cooled, and poured intowater. The resultant solid was collected. The solid was recrystallizedtwice from toluene to yield 2.4 g (23.7%) of product, mp 168°-170° C.

Analysis: Calculated for C₁₃ H₁₇ N₃ : 72.52% C, 7.96% H, 19.52% N.Found: 72.60% C, 8.04% H, 19.51% N.

EXAMPLE 5 3-[1-[4,4-bis(4-Fluorophenyl)butyl]-4-piperidinyl]-1H-indazole

A mixture of 10.0 g of 4-(2-fluorobenzoyl)piperidine, 16.9 g ofpotassium carbonate, 20.8 g of 4-chloro-1,1-bis(4-fluorophenyl)butane,250 ml of dimethylformamide and a few crystals of potassium iodide washeated at 90° for 8 hrs with stirring. The reaction mixture was pouredinto water and extracted with ethyl acetate. The ethyl acetate extractwas washed with water, dried over anhydrous magnesium sulfate and thesolvent removed in vacuo to yield an oil. The oil was dissolved inether, and oxalic acid was added. Recrystallization of the resultantsolid from ethanol gave 10.6 g (34.6%) of1-[4,4-bis(4-fluorophenyl)-1-butyl]-4-(2-fluorobenzoyl)piperidineoxalate, mp 179°-181° C.

A solution of 8.0 g of1-[4,4-bis(4-fluorophenyl)-1-butyl]-4-(2-fluorobenzoyl)piperidine and110 ml of hydrazine hydrate was heated at 150° in an autoclave for 20hrs, with stirring. The resultant solid was diluted with water, and themixture extracted with dichloromethane. The dichloromethane wasevaporated in vacuo to yield a solid. The solid was recrystallized fromtoluene to give 3.8 g (47.4%) of product, mp 154°-156° C.

Analysis: Calculated for C₂₈ H₂₉ F₂ N₃ : 75.48% C, 6.56% H, 9.43% N.Found: 75.29% C, 6.59% H, 9.40% N.

EXAMPLE 6 1-Ethyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrobromide

To a stirred suspension of 0.86 g of sodium hydride (50% oil dispersion)in 50 ml of dimethylformamide was added, dropwise, 3.0 g of3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of hotdimethylformamide. The reaction mixture was stirred at ambienttemperature and 1.34 ml of ethyl bromide in 10 ml of dimethylformamidewas added, dropwise. The reaction was stirred overnight at ambienttemperature and poured into water. The aqueous suspension was extractedwith ethyl acetate (2X, 100 ml). The extracts were combined, washed withwater, dried over anhydrous magnesium sulfate, and the solventevaporated in vacuo to yield an oil. The oil was dissolved in a minimumamount of ethanol-ether, and a saturated solution of ether-hydrogenbromide was added. The salt was recrystallized from ethanol-ether toyield 2.4 g (52.8%) of product, mp 240°-242° C.

Analysis: Calculated for C₁₅ H₂₁ N₃ HBr: 55.56% C, 6.84% H, 12.96% N.Found: 55.39% C, 6.68% H, 12.59% N.

EXAMPLE 7 1-(4-Nitrophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

To a stirred suspension, under nitrogen, of 0.86 g of sodium hydride(50% oil dispersion) was added, dropwise, 3.2 g of3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hotdimethylformamide. After completion of the addition, the reactionmixture was stirred at ambient temperature for 1 hr and then 2.2 g of1-fluoro-4-nitrobenzene was added, dropwise. The reaction mixture wasstirred at ambient temperature for 16 hr and then poured into water. Theresultant solid was collected and dried. The solid was dissolved inabsolute ethanol and the solution was treated with saturated hydrogenchloride/ether solution to precipitate a salt. Recrystallization of thesalt from methanol-ether (twice) gave 3.0 g (52%) of product, mp272°-274° C.

Analysis: Calculated for C₁₉ H₂₀ N₄ O₂.HCl: 61.20% C, 5.68% H, 15.03% N.Found: 61.09% C, 5.70% H, 14.82% N.

EXAMPLE 81-[3-(Dimethylamino)propyl]-3-(1-methyl-4-piperidinyl)-1H-indazoledifumarate

To a stirred suspension of 1.15 g of sodium hydride (50% oil dispersion)in 30 ml of dimethylformamide, under nitrogen, was added dropwise 4.3 gof 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 30 ml of hotdimethylformamide. After stirring at ambient temperature for 1 hr, asolution of 3.3 g of dimethylaminopropylchloride in 30 ml of toluene wasadded dropwise. The reaction was then heated at 60° for 1 hr and thenstirred at ambient temperature for 16 hrs. The reaction mixture waspoured into water and the aqueous suspension was extracted with ethylacetate (3×150 ml). The organic extracts were combined, washed withwater, brine, dried over anhydrous magnesium sulfate, and the solventevaporated in vacuo to yield an oil. The oil was dissolved in 25 ml ofacetonitrile and 4.6 g of fumaric acid was added. The mixture was warmedon the steam bath (ca. 15 min), and then left at ambient temperature for15 hrs. The resultant solid was filtered and recrystallized fromdimethylformaide (thrice) with cooling (ca. 5°) to yield 1.4 g (18.7%)of product, mp 161°-163° C.

Analysis: Calculated for C₁₈ H₂₈ N₄.2C₄ H₄ O₄ : 58.61% C, 6.81% H,10.52% N. Found: 58.82% C, 6.91% H, 11.51% N.

EXAMPLE 93-(1-Methyl-4-piperidinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazolehydrochloride

To a stirred suspension of 1.15 g of sodium hydride (50% oil dispersion)in 30 ml of dimethylformamide, under nitrogen, was added dropwise 4.3 gof 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 30 ml of hotdimethylformamide. The reaction mixture was stirred at ambienttemperature for 1 hr and then 3.9 g of 4-fluorobenzotrifluoride wasadded. The temperature was raised to 90° and held there for 16 hrs. Thereaction mixture was poured into water and the aqueous suspensionextracted with ethyl acetate (2x, 150 ml). The extracts were combined,washed with water, brine, dried over anhydrous magnesium sulfate and thesolvent removed in vacuo to yield an oil. The oil was dissolved in etherand saturated ether-hydrogen chloride solution was added to precipitatea salt. Recrystallization (twice) from isopropanol-ether gave 3.3 g(41.7%) of product, mp 221°-223° C.

Analysis: Calculated for C₂₀ H₂₀ F₃ N₃.HCl: 60.68%C, 5.34%H, 10.62%N.Found: 60.86%C, 5.55%H, 10.62%N.

EXAMPLE 10 1-Hydroxymethyl-3-(1-methyl-4-piperidinyl)-1H-indazole

A solution of 0.52 g of paraformaldehyde, 3.0 g of3-(1-methyl-4-piperidinyl)-1H-indazole, 15 ml of ethanol and 0.34 ml of5% aqueous sodium hydroxide was refluxed for 3 hrs. The ethanol wasremoved in vacuo and the residue diluted with water. The aqueoussuspension was extracted with dichloromethane (2x, 50 ml) and thecombined extracts were washed with water and dried over anhydrousmagnesium sulfate. The dichloromethane was evaporated in vacuo to yieldan oil, which crystallized upon standing. The solid was recrystallizedtwice from ethyl acetate to yield 1.3 g (57.8%) of product, mp 128°-130°C.

Analysis: Calculated for C₁₄ H₁₉ N₃ O: 68.54%C, 7.81%H, 17.13%N. Found:68.41%C, 7.81%H, 17.24%N.

EXAMPLE 111-(6-Fluoro-1,2-benzisoxazole-3-propyl)-3-(1-methyl-4-piperidinyl)-1H-indazolemaleate

To a stirred suspension under nitrogen of 0.8 g of sodium hydride (50%oil dispersion) in 45 ml of dimethylformamide, was added dropwise, 3.0 gof 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 10 ml of hotdimethylformamide. The reaction mixture was stirred at ambienttemperature for 45 min and then 3.9 g of3-(3-chloroprop-1-yl)-6-fluoro-1,2-benzisoxazole was added. The reactionmixture was stirred at ambient temperature overnight (ca. 16 hr) andthen poured into water. The aqueous suspension was extracted with etherand the ether extract was washed with water, dried over anhydrousmagnesium sulfate, and filtered. Trreatment of the ethereal solutionwith 2.0 g of maleic acid suspended in 10 ml of ethanol resulted in anoil. Decantation of the supernatant ether solution and subsequenttrituration of the oil with ethyl acetate gave a solid.Recrystallization of the solid from ethyl acetate yielded 3.0 g (43%) ofproduct, mp 127°-129° C.

Analysis: Calculated for C₂₃ H₂₅ FN₄ O.C₄ H₄ O₄ : 63.77%C, 5.75%H,11.02%N. Found: 63.53%C, 5.71%H, 11.15%N.

EXAMPLE 12 1-Cyclopropylmethyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrobromide

To a stirred mixture of 1.19 g of sodium hydride (50% oil dispersion) in65 ml of dimethylformamide was added, dropwise, 4.0 g of3-(1-methyl-4-piperidinyl)-1H-indazole in 20 ml of hotdimethylformamide. The mixture was stirred for 1 hr at ambienttemperature and then 1.40 g of chloromethylcyclopropane in 10 ml ofdimethylformamide was added dropwise. The reaction mixture was stirredfor 21/2 days at ambient temperature. The reaction mixture was quenchedwith water, extracted with ethyl acetate, washed with water, dried overanhydrous magnesium sulfate and the solvent was removed in vacuo toyield an oil. The oil was dissolved in ether and saturated hydrogenbromide/ether solution. was added dropwise to precipitate a salt. Thesalt was recrystallized from toluene and ethyl acetate to yield 2.8 g(32%) of product, mp 177°-179° C.

Analysis: Calculated for C₁₇ H₂₃ N₃.HBr: 58.29% C, 6.86%H, 12.00%N.Found: 58.20%C, 6.59%H, 11.82%N.

EXAMPLE 13 1-Phenylmethyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrobromide

To a stirred suspension of 0.86 g of sodium hydride (50% oil dispension)in 50 ml of dimethylformamide under nitrogen, was added, dropwise, 3.0 gof 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 15 ml of hotdimethylformamide. After stirring one hr at ambient temperature, 2.6 gof benzyl bromide in 5 ml of dimethylformamide was added. The reactionmixture was stirred at ambient temperature for 15 hrs. and then pouredinto water. The aqueous mixture was extracted with ethyl acetate. Theethyl acetate extract was washed with water, brine and dried overanhydrous magnesium sulfate. The ethyl acetate was evaporated in vacuoto yield an oil. The oil was dissolved in ether and gaseous hydrogenbromide was passed through the solution to yield an oily material. Theoily material was triturated with boiling ethyl acetate. The solid wascollected and recrystallized from absolute ethanol to yield 2.4 g(44.3%) of product, mp 218°-220° C.

Analysis: Calculated for C₂₀ H₂₃ N₃.HBr: 62.18%C, 6.00%H, 10.88%N.Found: 62.13%C, 6.24%H, 10.87%N.

EXAMPLE 14 1-(2-Phenylethyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrobromide

To a stirred mixture of 0.86 g of sodium hydride (50% oil dispersion) in50 ml of dimethylformamide was added, dropwise, 3.0 g of3-(1-methyl-4-piperidinyl)-1H-indazole in 15 ml of hotdimethylformamide. The reaction mixture was stirred at ambienttemperature for 1 hr and then a solution of 3.33 g of(2-bromoethyl)benzene in 10 ml of dimethylformamide was added dropwise.The reaction mixture was stirred for 21/2 days at ambient temperature,cooled to 0°, and water was added dropwise. The mixture was extractedwith ethyl acetate, washed with water, dried over anhydrous magnesiumsulfate and the solvent was removed in vacuo to yield an oil. The oilwas dissolved in ether and a saturated hydrogen bromide/ether solutionwas added dropwise. The resultant solid was recrystallized two timesfrom ethanol to yield 2.0 g (36%) of product, mp 163°-164° C.

Analysis: Calculated for C₂₁ H₂₅ N₃.HBr: 63.00%C, 6.50%H, 10.50%N.Found: 62.93%C, 6.58%H, 10.55%N.

EXAMPLE 15 1-Acetyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride

A mixture of 2.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole, 20 ml ofacetic anhydride and a few drops of pyridine was stirred under refluxfor 2 hrs. Most of the acetic anhydride was evaporated in vacuo and theresultant solution was poured into 80 ml of water. The solution was madebasic with ammonium hydroxide solution. A white solid precipitated. Thesolid was collected, dried and dissolved in ether. Saturatedether-hydrogen chloride solution was added. The salt was reprecipitatedfrom cold methanol with ether to yield 1.6 g (60.5%) of product, mp238°-239° C.

Analysis: Calculated for C₁₅ H₁₉ N₃ O.HCl: 61.32%C, 6.86%H, 14.30%N.Found: 61.08%C, 6.76%H, 14.32%N.

EXAMPLE 16 1-Benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 3.2 mlof benzoyl chloride was heated at 100° for 2 hrs. The resultant solidwas triturated with ether and collected. The salt was twicerecrystallized from ethanol-ether to yield 3.1 g (62.2%) of product, mp234°-236° C.

Analysis: Calculated for C₂₀ H₂₁ N₃ O.HCl: 67.50%C, 6.23%H, 11.81%N.Found: 67.22%C, 6.15%H, 11.82%N.

EXAMPLE 173-(1-Methyl-4-piperidinyl)-1-trichloroethoxycarbonyl-1H-indazolehydrochloride

A mixture of 2.3 g of trichloroethyl chloroformate, 3.0 g of potassiumcarbonate, 2.1 g of 3-(1-methyl-4-piperidinyl)-1H-indazole andchloroform was heated under reflux for 16 hrs. The reaction mixture wascooled, filtered, and the filtrate was concentrated to a solid in vacuo.The solid was triturated with ethyl acetate, collected, andrecrystallized from ethanol to yield 3.9 g (91%) of product, mp190°-192° C.

Analysis: Calculated for C₁₆ H₁₈ Cl₃ N₃ O₂.HCl: 44.99%C, 4.48%H, 9.85%N.Found: 44.64%C, 4.46%H, 9.84%N.

EXAMPLE 18 1-Phenylsulfonyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A mixture of 2.5 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 50 mlof benzenesulfonyl chloride was heated on a steam bath for 1 hr. Thesolution was cooled to ambient temperature and then poured into ether.The precipitate was collected and triturated with ethyl acetate to yielda solid. The solid was combined with 1.5 g of solid from anotherexperiment and recrystallized twice from isopropanol to yield 2.3 g(36%) of product, mp 222°-224° C.

Analysis: Calculated for C₁₉ H₂₁ N₃ O₂ S: 58.24%C, 5.66%H, 10.72%N.Found: 58.17%C, 5.77%H, 10.80%N.

EXAMPLE 19 1-(4-Fluorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazole

A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 15 mlof 4-fluorobenzoyl chloride was heated at 100° for 2 hrs. The reactionmixture was poured into ether and the precipitate was collected. Theprecipitate was treated with dilute aqueous sodium hydroxide solutionand extracted with chloroform. The chloroform extract was dried overanhydrous magnesium sulfate and the solvent removed in vacuo to yield2.5 g (53%) of product, mp 132°-133° C.

Analysis: Calculated for C₂₀ H₂₀ FN₃ O: 71.20%C, 5.98%H, 12.45%. Found:71.42%C, 6.21%H, 12.50%N.

EXAMPLE 20 1-Ethoxycarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

To a stirred mixture of the 3.5 g of3-(1-methyl-4-piperidinyl)-1H-indazole, 2.7 g of potassium carbonate and40 ml of chloroform was added, dropwise, 21.1 g of ethyl chloroformate.The reaction mixture was stirred under reflux for 16 hr, cooled,filtered, and the filtrate was concentrated in vacuo. The residue wastriturated with ether. Recrystallization from ethanol-ether and thenfrom isopropyl alcohol-ether gave 2.3 g (43.8%) of product, mp 181°-183°C. (gas evolution).

Analysis: Calculated for C₁₆ H₂₁ N₃ O₂.HCl: 59.34%C, 6.85%H, 12.98%N.Found: 58.76%C, 7.05%H, 12.80%N.

EXAMPLE 21 1-(4-Methoxybenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 10 mlof p-anisoyl chloride was heated at 100° C. for 3 hr. The reactionmixture was cooled to ambient temperature, ether was added and the solidwas collected. The solid, suspended in ether, was stirred for 16 hr. Themixture was filtered, and dried. Recrystallization from ethanol (twice)yielded 4.0 g (74.4%) of product, mp 235°-237° C.

Analysis: Calculated for C₂₁ H₂₃ N₃ O₂.HCl: 65.36%C, 6.27%H, 10.89%N.Found: 64.83%C, 6.16%H, 10.82%N.

EXAMPLE 22 1-(2-Chlorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

To a stirred suspension of 1.1 g of sodium hydride (50% oil dispersion)in 40 ml of dimethylformamide under nitrogen was added, dropwise, 4.0 gof 3-(1-methyl-4-piperidinyl)-1H-indazole in 25 ml of hotdimethylformamide. The reaction was stirred at ambient temperature for 1hr and then 3.6 g of 1-chloro-2-fluorobenzene was added. The temperaturewas then raised to 120° and held at 120° for 20 hrs. The reaction waspoured into water and the aqueous suspension was extracted with ether.The ether extract was washed with water, dried over anhydrous magnesiumsulfate, and the ether was removed in vacuo. The residue waschromatographed on a Water's preparative high-pressure liquidchromatograph using a silica gel columns eluted with tetrahydrofuran-(C₂H₅)₂ NH (99:1). Evaporation of the appropriate fractions yielded an oil.The oil was dissolved in ether and 1.5 g of fumaric acid was added. Themixture was stirred at ambient temperature for 16 hr., and the solid wascollected. Recrystallization from isopropyl alcohol-ether and then fromethanol-ether gave 2.5 g (31.4%) of product, mp 179°-181° C.

Analysis: Calculated for C₁₉ H₂₀ ClN₃.C₄ H₄ O₄ : 62.51%C, 5.47%H,9.51%N. Found: 62.46%C, 5.50%H, 9.43%N.

EXAMPLE 23 4-(1-Benzoyl-1H-indazol-3-yl)piperidine-1-carbonitrile

A sample of 8.4 g of 1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride was converted to its free base and the base was dissolvedin 135 ml of chloroform. The solution was stirred and 4.0 g of potassiumcarbonate was added followed by 2.7 g of cyanogen bromide. The reactionmixture was stirred under reflux for 16 hrs. The mixture was filtered,and the solvent was removed in vacuo. The mixture was chromatographed ona high-pressure column chromatography apparatus (silica gel), elutingwith 0.3% methanol/dichloromethane. Evaporation of the appropriatefraction followed by recrystallization from toluene hexane yielded 2.2 g(28%) of the product, mp 144°-146° C.

Analysis: Calculated for C₂₀ H₁₈ N₄ O: 72.71%C, 5.59%H, 16.97%N. Found:72.56%C, 5.57%H, 17.18%N.

EXAMPLE 24 6-Fluoro-3-(4-piperidinyl)-1H-indazole

A solution of 20.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, 60ml of hydrazine hydrate and 150 ml of n-butanol was refluxed for 48 hrs.The reaction was poured into 11 of water, and the mixture was extractedwith ethyl acetate. The ethyl acetate extract was washed with water,dried over anhydrous magnesium sulfate and the solvent was evaporated invacuo. Recrystallization of the residue from isopropanol-water and thenfrom isopropanol yielded 3.3 g (20.1%) of product, mp 214°-216° C.

Analysis: Calculated for C₁₂ H₁₄ N₃ F: 65.73%C, 6.44%H, 19.17%N. Found:65.55%C, 6.35%H, 19.30%N.

EXAMPLE 25 1-(2-Furoyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A mixture of 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole, 2.7 ml of2-furoyl chloride (95% pure) and 60 ml of chloroform was refluxed for 3hrs. The mixture was filtered. The filtrate was evaporated under reducedpressure, the residue was triturated with ethyl acetate and the solidwas collected. The solid and filtrate were combined and recrystallizedtwice from ethanol to yield 3.3 g (51.5%) of product, mp 268°-270° C.

analysis: Calculated for C₁₈ H₁₉ N₃ O₂. HCl: 62.51%C, 5.83%H, 12.15%N.Found: 62.78%C, 6.00%H, 12.11%N.

EXAMPLE 26 1-(4-Chlorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

To a stirred suspension of 1.1 g of sodium hydride (50% oil dispersion)in 40 ml of dimethylformamide was added, dropwise, under nitrogen, 4.0 gof 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hotdimethylformamide. The reaction was stirred at ambient temperature for45 min, and 2.9 ml of 4-fluorochlorobenzene was added. The temperaturewas increased to 120° and the reaction proceeded at this temperature for24 hr. The reaction was poured into water and the aqueous mixture wasextracted with ethyl acetate. The ethyl acetate extract was washed withwater, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue was heated (steam bath) with 3N hydrochloric acid and thesalt was collected. The salt was immediately recrystallized from water.The wet salt was treated with ammonium hydroxide and the base wasextracted into dichloromethane. Evaporation of the dichloromethane invacuo gave an oil. The oil solidified on standing. The solid wasdissolved in ether and 1.4 g of fumaric acid was added.Recrystallization from 2-propanol gave 3.9 g (47.5%) of product, mp176°-178° C.

Analysis: Calculated for C₁₉ H₂₀ ClN₃.C₄ H₄ O₄ : 62.25%C, 5.47%H,9.51%N. Found: 62.32%C, 5.40%H, 9.56%N.

EXAMPLE 27 6-Fluoro-3-[1(1-propyl)-4-piperidinyl]-1H-indazole

A mixture of 3.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 1.8 g of1-bromopropane, 2.5 g of sodium bicarbonate and 30 ml ofdimethylformamide was stirred and heated at 60° for 2 hr. After stirringat ambient temperature for 14 hr, the reaction was poured into water andthe aqueous suspension was extracted with ethyl acetate. The ethylacetate was washed with water, dried over anhydrous magnesium sulfateand the solvent was removed in vacuo. Recrystallization of the residuefrom ethyl acetate yielded 2.3 g (63%) of product. This material wascombined with a sample from another experiment and recrystallized fromethyl acetate to yield the analytical sample, mp 175°-177° C.

Analysis: Calculated for C₁₅ H₂₀ FN₃ : 68.94%C, 7.71%H, 16.08%N. Found:69.24%C, 7.62%H, 16.15%N.

EXAMPLE 28 6-Fluoro-3-[1-(2-phenylethyl)-4-piperidinyl]-1H-indazole

A mixture of 5.0 g of 6-fluoro-3-(4-piperidinyl)-1H-indazole, 4.6 g of(2-bromoethyl)benzene, 4.2 g of sodium bicarbonate and 50 ml ofdimethylformamide was stirred at 60° for 3 hr and at ambient temperaturefor 14 hr. The reaction was poured into water and the aqueous mixtureextracted with ethyl acetate. The ethyl acetate was washed with water,dried over anhydrous magnesium sulfate and the solvent was removed invacuo. The residue was recrystallized twice from 2-propanol (onecharcoal treatment) to yield 2.6 g (35%) of product, mp 163°-165° C.

Analysis: Calculated for C₂₂ H₂₂ FN₃ : 74.27%C, 6.86%H, 12.99%N. Found:74.45%C, 6.96%H, 13.49%N.

EXAMPLE 29 1-Benzoyl-3-[1-(2-phenylethyl)-4-piperidinyl]-1H-indazolehydrochloride

A mixture of 1.6 g of 3-(1-pheneth-2-yl-4-piperidinyl)-1H-indazole and 7ml of benzoyl chloride was heated at 100° for 2 hr. After cooling, etherwas added and the solid was collected. The solid was combined withmaterial from a prior experiment and recrystallized from methanol toyield 2.4 g (51%) of product, mp 248°-250° C.

Analysis: Calculated for C₂₇ H₂₆ FN₃ O.HCl: 69.89%C, 5.86%H, 9.06%N.Found: 70.03%C, 5.96%H, 9.22%N.

EXAMPLE 30 1-(3-Chlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of3-chlorobenzoyl chloride was heated at 100° C. for 2 hours. The reactionws allowed to cool, and ether was added. The resultant solid wascollected and recrystallized twice from isopropyl alcohol to yield 3.7 g(67.7%) of product, mp 209°-211° C.

Analysis: Calculated for C₂₀ H₂₀ ClN₃ O. HCl: 61.54%C, 5.42%H, 10.77%N.Found: 61.54%C, 5.57%H, 10.66%N.

EXAMPLE 31 1-(2-Chlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

A mixture of 3.0 g of 3-(4-piperidinyl)-1H-indazole and 8 ml of2-chlorobenzoyl chloride was heated at 100° (steam bath) for 2 hr. Thereaction was cooled to ambient temperature, and ether was added. Theoil, which separated, solidified upon scratching. The solid was treatedwith ammonium hydroxide and the precipitate was dissolved inether-ethanol (350:10 ml). Fumaric acid (1.4 g) was added, and themixture was stirred at ambient temperature for 4 hr. The resultant solidwas collected, dried, triturated with hot acetone, and recrystallizedfrom isopropyl alcohol to yield 3.6 g (54.7%) of the product, mp182°-184° C.

Analysis: Calculated for C₂₀ H₂₀ ClN₃ O.C₄ H₄ O₄ : 61.34%C, 5.15%H,8.94%N. Found: 61.54%C, 5.30%H, 8.96%N.

EXAMPLE 32 6-Fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred suspension, under nitrogen, of 4.7 g of lithium aluminumhydride (50-55% oil dispersion) in 90 ml of tetrahydrofuran was added,dropwise, 8.9 g of6-fluoro-3-(1-methoxycarbonyl-4-piperidinyl)-1H-indazole, dissolved in50 ml of tetrahydrofuran. After the addition was complete, the reactionwas heated under reflux for 2 hr. The reaction was cooled in an ice-saltbath and water was carefully added. The mixture was filtered and thefilter cake was washed with tetrahydrofuran and twice with hot methanol.The filtrate was concentrated in vacuo. The residue was triturated withethyl acetate to yield 5.1 g (68%) of product, mp 217°-220°.Recrystallization from ethanol (twice) provided the analytical sample,mp 218°-220° C.

Analysis: Calculated for C₁₃ H₁₆ FN₃ : 66.93%C, 6.91%H, 18.01%N. Found:67.08%C, 6.97%H, 18.09%N.

EXAMPLE 33 1-(2-Nitrophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

To a stirred suspension, under nitrogen, of 0.86 g of a 50% oildispersion of sodium hydride in 20 ml of dimethylformamide was added,dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in25 ml of hot dimethylformamide. Upon completion of the addition, thereaction mixture was stirred at ambient temperature for one hr and asolution of 2.2 g of 1-fluoro-2-nitrobenzene in 5 ml ofdimethylformamide was added slowly. The reaction mixture was stirred atambient temperature for 2 hrs and then poured into water. Theprecipitate was collected and then dissolved in ethanol-ether. To thestirred solution, 1.7 g of fumaric acid was added. After stirring atambient temperature for four hrs, the mixture was filtered and thefilter cake was recrystallized from methanol-ether (twice) to yield 4.3g (67.8%) of product, mp 210°-212° C.

Analysis: Calculated for C₁₉ H₂₀ N₄ O₂.C₄ H₄ O₄ : 61.05%C, 5.35%H,12.38%N. Found: 61.08%C, 5.43%H, 12.47%N.

EXAMPLE 34 1-(2-Chlorophenyl)-3-(4-piperidinyl)-1H-indazole fumarate

To a stirred mixture of 4.2 g of cyanogen bromide, 6.3 g of potassiumcarbonate and 125 ml of dimethylsulfoxide was added, dropwise, 12.0 g of1-(2-chlorophenyl)-3-(1- methyl-4-piperidinyl)-1H-indazole dissolved in30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambienttemperature for two hrs and then poured into water. The aqueous mixturewas extracted with ethyl acetate. The ethyl acetate extracts were washedwith water, dried over anhydrous magnesium sulfate, and the solvent wasremoved in vacuo to give an oil. The oil was triturated with ether togive 7.1 g (57%) of4-[2-(2-chlorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, mp109°-111° C.

A stirred mixture of 6.5 g of4-[2(2--chlorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile and 60ml of 25% aqueous sulfuric acid was heated under reflux for 16 hr. Thereaction mixture was cooled in an ice-bath and 50% aqueous sodiumhydroxide solution was added dropwise until the mixture was basic. Theaqueous mixture was extracted with ethyl acetate. The extracts werewashed with water, dried over anhydrous magnesium sulfate and thesolvent removed in vacuo to give an oil. The oil was dissolved inethanol-ether and 2.2 g of fumaric acid was added. After stirring atambient temperature for 6 hrs, the salt was collected. The salt wasrecrystallized twice from methanol-ether to yield 2.4 g (30%) ofproduct, mp 213°-215° C.

Analysis: Calculated for C₁₈ H₁₈ ClN₃.C₄ H₄ O₄ : 61.75%C, 5.18%H,9.82%N. Found: 61.55%C, 5.48%H, 9.62%N.

EXAMPLE 35 1-(2-Aminophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

To a cooled (5° C), stirred solution of 9.5 g of stannous chloridedihydrate in 20 ml of concentrated hydrochloric acid and 10 ml oftetrahydrofuran was added, dropwise, 3.6 g of1-(2-nitro-phenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in25 ml of teterahydrofuran. After completion of the addition, the coolingbath was removed and the reaction mixture was stirred at ambienttemperature of 3 hrs. The reaction mixture was poured into ice water andmade basic with 10% sodium hydroxide solution. The mixture was extractedwith ethyl acetate. The extract was washed with water, dried overanhydrous magnesium sulfate and the solvent was removed in vacuo. Theresidue was dissolved in ethanol (warming) and 2.0 g of fumaric acid wasadded. The mixture was then warmed on the steam bath for a few mins. Thesalt was collected to give 3.4 g (80%) of product. The salt was combinedwith 1.1 g of another experiment and recrystallized first fromdimethylformamide-ethyl acetate (twice) and then from methanol-ether toyield the analytical sample, mp 208°-210° C.

Analysis: Calculated for C₁₉ H₂₂ N₄.C₄ H₄ O₄ :65.40%C, 6.21%H, 13.24%N.Found: 65.46%C, 6.40%H, 13.35%N.

EXAMPLE 36 1-(2-Fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

To a stirred suspension of 1.0 g of a 50% oil dispersion of sodiumhydride in 20 ml of dimethylformamide, under nitrogen, was added,dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in25 ml of hot dimethylformamide. After ageing at ambient temperature for45 mins, 3.6 g of 1,2-difluorobenzene was added and the temperature wasraised to 120° C. and held there for 6 hrs. The reaction mixture wasquenched with water and the aqueous mixture extracted with ether. Theether extract was washed with water, dried over anhydrous magnesiumsulfate and the solvent removed in vacuo to yield an oil. The oil wascombined with 2.7 g of oil from another experiment and the combinedsample (6.9 g) was chromatographed. Flash chromatography was utilizedwith 210 g of silica gel and ethyl acetate-diethylamine (10%) as theeluent. Evaporation of the appropriate fractions gave 4.3 g (57%) ofproduct, as an oil. Treatment of the oil with ethereal hydrogen chloridegave the hydrochloride salt. The salt was recrystallized fromethanol-ether and then from acetonitrile to yield the analytical sample,mp 215°-217° C.

Analysis: Calculated for C₁₉ H₂₀ FN₃.HCl: 65.98%C, 6.11%H, 12.16%N.Found: 65.79%C, 6.16%H, 12.21%N.

EXAMPLE 37 1-(3-Fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

To a suspension of 2.0 g of a 50% oil dispersion of sodium hydride in 40ml of dimethylformamide was added, dropwise, 6.4 g of3-(1-methyl-4-piperidinyl)-1H-indazole in 50 ml of hotdimethylformamide. After stirring for 40 mins at ambient temperature,7.2 g of 1,3-difluorobenzene was added. The mixture was heated at 120°C. for 20 hrs, cooled and poured into water. The mixture was extractedwith ether. The extracts were dried over anhydrous magnesium sulfate andconcentrated to yield an oil. The oil was purified using flashchromatography (silica gel, diethylamine-ethyl acetate, 1:9).Evaporation of appropriate fractions gave an oil. The oil was dissolvedin anhydrous ether and hydrogen chloride gas was bubbled into thesolution. The ether was decanted and the solid was recrystallized twicefrom ethanol-ether to yield 2.6 g (25%) of product, mp 254°-256° C.

Analysis: Calculated for C₁₉ H₂₀ FN₃.HCl: 65.99%C, 6.12%H, 12.15%N.Found: 65.83%C, 6.09%H, 12.15%N.

EXAMPLE 386-Fluoro-1-(2-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

To a stirred suspension, under nitrogen, of 1.2 g of a 50% oildispersion of sodium hydride in 25 ml of dimethylformamide was added,dropwise, 4.2 g of 6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazoledissolved in 30 ml of hot dimethylformamide. The reaction mixture wasstirred at ambient temperature for 45 mins and then 4.4 g of1,2-difluorobenzene was added. The temperature was raised to 120° C. andheld there for 6 hrs. The reaction mixture was poured into water and theaqueous mixture was extracted with ethyl acetate. The extract was washedwith water, dried over anhydrous magnesium sulfate and the solventconcentrated to yield an oil. The oil was triturated with hexane toyield 1.3 g of the indazole starting material. The filtrate wasconcentrated to an oil. The oil was purified by flash chromatographyutilizing a silica gel column (50×145 mm) and ethyl acetate-diethylamine(10%) as the eluent. Concentration of the appropriate fractions gave 2.0g (33%) of product, as an oil. The oil was dissolved in ether, stirred,and 0.8 g of fumaric acid was added. The salt was collected, dried andhad mp 181°-183° C.

Analysis: Calculated for C₁₉ H₁₉ F₂ N₃.C₄ H₄ O₄ : 62.29%C, 5.23%H,9.48%N. Found: 62.15%C, 5.40%H, 9.47%N.

EXAMPLE 39 1-Acetyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine

To a stirred solution of 3.0 g of1-acetyl-4-(2,4-difluorobenzoyl)piperidine phenylhydrazone in 30 ml ofdimethylformamide, under nitrogen, was added 0.44 g of a 50% oildispersion of sodium hydride. The reaction mixture was heated, and atabout 40° C. a vigorous evolution of hydrogen occurred. The temperaturewas then raised to 80° C. and held there for 1.5 hrs. The reactionmixture was poured into water and the aqueous suspension was extractedwith ethyl acetate. The ethyl acetate extracts were washed with water,dried over anhydrous magnesium sulfate and concentrated to yield an oil.The oil was combined with the oil from another experiment and a total of13.5 g of material was chromatogrphed on a Water's Prep LC 500. Twosilica gel columns were utilized and dichloromethane-methanol (3%) wasused as the eluent. The appropriate fractions were evaporated. Theresidue was recrystallized twice from isopropyl alcohol-water (onecharcoal treatment) to yield 2.4 g (18%) of product, mp 126°-128° C.

Analysis: Calculated for C₂₀ H₂₀ FN₃ O: 71.20%C, 5.98%H, 12.45%N. Found:70.98%C, 5.99%H, 12.48%N.

EXAMPLE 401-[2-(Trifluoromethyl)phenyl]-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred suspension of 1.0 g of a 50% oil dispersion of sodiumhydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hotdimethylformamide. After stirring for one hr at ambient temperature,3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture washeated to 90° C. and stirred for 17 hrs. The mixture was then pouredinto water, extracted with ether, dried over anhydrous magnesium sulfateand concentrated. The residue was purified using flash chromatography(silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractionswere evaporated. The residue was recrystallized once from hexane, thencombined with a previously prepared sample (1.1 g), and recrystallizedfrom hexane to yield 2.17 g of (24%) of product, mp 110°-111° C.

Analysis: Calculated for C₂₀ H₂₀ F₃ N₃ : 66.84%C, 5.61%H, 11.69%N.Found: 66.65%C, 5.59%H, 11.82%N.

EXAMPLE 411-(2-Fluorophenylmethyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrobromide

To a suspension of 0.86 g of a 50% oil dispersion of sodium hydride in50 ml of dimethylformamide was added, dropwise, 3.0 g of3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 15 ml of hotdimethylformamide. After stirring for 1 hr, 2.19 g of 2-fluorobenzylchloride was added. The reaction mixture was stirred at ambienttemperature for 17 hrs and then poured into 250 ml of water. The mixturewas extracted with ether. The extract was washed with water, brine anddried over anhydrous magnesium sulfate. The solvent was evaporated. Theresidue was dissolved in anhydrous ether and hydrogen bromide gas wasbubbled through the solution. The salt was triturated with ether andrecrystallized from ethanol-ether and then ethanol to yield 3.06 g (54%)of product, mp 205°-206° C.

Analysis: Calculated for C₂₀ H₂₂ FN₃.HBr: 59.41%C, 5.73%H, 10.39%N.Found: 59.02%C, 5.68%H, 10.29%N.

EXAMPLE 42 1-Benzoyl-6-chloro-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A mixture of 3.0 g of 6-chloro-3-(1-methyl-4-piperidinyl)-1H-indazoleand 8 ml of benzoyl chloride was heated at 100° C. on a steam bath for 4hrs. The reaction mixture was cooled to ambient temperature and etherwas added. The precipitate was filtered, washed with ether and dried.Recrystallization from ethanol (twice) yielded 2.6 g (56%) of product,mp 248°-250° C.

Analysis: Calculated for C₂₀ H₂₀ ClN₃ O.HCl: 61.54%C, 5.42%H, 10.77%N.Found: 61.34%C, 5.46%H, 10.67%N.

EXAMPLE 431-(4-Chlorobenzoyl)-3-(1-ethyl-4-piperidinyl)-6-fluoro-1H-indazolehydrochloride

A mixture of 3.0 g of 3-(1-ethyl-4-piperidinyl)-6-fluoro-1H-indazole and8 ml of 4-chlorobenzoyl chloride was heated at 100° C. in a steam bathfor 4 hrs. Ether was added and the solid was collected. The solid wasrecrystallized twice from ethanol-ether to yield 2.9 g (57%) of product,mp 240°-242° C.

Analysis: Calculated for C₂₁ H₂₁ ClFN₃ O.HCl: 59.72%C, 5.01%H, 9.95%N.Found: 59.69%C, 5.39%H, 9.92%N.

EXAMPLE 441-(4-Chlorobenzoyl)-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A mixture of 2.0 g of 6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazoleand 5 ml of 4-chlorobenzoyl chloride was heated at 100° C. in a steambath for 2 hrs. After cooling, ether was added and the solid wascollected. The solid was combined with a 2.5 g sample from anotherexperiment and recrystallized twice from ethanol-ether to yield 4.7 g(56%, calculated on the combination of both experiments) of product, mp258°-260° C.

Analysis: Calculated for C₂₀ H₁₉ ClN₃.HCl: 58.83%C, 4.69%H, 10.29%N.Found: 59.02%C, 5.07%H, 10.30%N.

EXAMPLE 45 1-(4-Methylbenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of4-toluoyl chloride was heated at 100° C. on a steam bath for 4 hrs.Ether was added to the cooled mixture and the salt was collected. Thesalt was converted to its free base by means of ammonium hydroxidesolution. The base was dissolved in ethanol (90 ml)-ether (175 ml) and1.5 g of fumaric acid was added. The mixture was stirred at ambienttemperature for 16 hrs, and the resultant fumarate salt was collected.Recrystallization twice from methanol-ether yielded 3.8 g (60%) ofproduct, mp 205°-207° C.

Analysis: Calculated for C₂₁ H₂₃ N₃ O.C₄ H₄ O₄ : 66.80%C, 6.06%H,9.35%N. Found: 66.98%C, 6.14%H, 9.44%N.

EXAMPLE 461-(3,4-Dichlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazole

A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of3,4-dichlorobenzoyl chloride was heated at 100° C. in a steam bath for 4hrs. After the reaction mixture cooled to ambient temperature, ether wasadded and the salt was collected. The salt was mixed with water andammonium hydroxide solution was added until the mixture was basic. Themixture was warmed on the steam bath for about 5 mins, cooled andextracted with dichloromethane. Evaporation of the dichloromethane invacuo provided the free base. The base was recrystallized frommethanol-trichloromethane (with concentration of the mother liquor) toyield 3.0 g (57%) of product, mp 187°-189° C.

Analysis: Calculated for C₂₀ H₁₉ Cl₂ N₃ O: 61.86%C, 4.93%H, 10.82%N.Found: 61.83%C, 5.02%H, 10.84%N.

EXAMPLE 47 1-Benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

A mixture of 3.1 g of 6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazoleand 8 ml of benzoyl chloride was heated at 100° C. in a steam bath for 8hrs. After cooling, ether was added and the solid was collected. Thesolid was treated with ammonium hydroxide solution to give an oil. Theoil was dissolved in 300 ml of ether, stirred and 1.2 g of fumaric acidwas added. After four hrs at ambient temperature, the fumarate salt wascollected. Recrystallization from ethanol-ether yielded 3.0 g (50.9%) ofproduct, mp 180°-182° C.

Analysis: Calculated for C₂₀ H₂₀ FN₃ O.C₄ H₄ O₄ : 63.57%C, 5.33%H,9.27%N. Found: 63.51%C, 5.43%H, 9.53%N.

EXAMPLE 481-[4-(Trifluoromethyl)benzoyl]-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of4-trifluoromethylbenzoyl chloride was heated at 100° C. on a steam bath.After 2 hrs, an additional 5 ml of 4-trifluoromethylbenzoyl chloride wasadded and heating was continued for two additional hrs. After cooling toambient temperature, ether was added and the salt was collected. Thesalt was converted to its free base by means of ammonium hydroxidesolution. The free base was dissolved in ethanol-ether and 0.75 g offumaric acid was added to give 2.7 g (38%) of product. Two samples ofthe salt were combined and recrystallized from ethanol (twice) to yieldthe analytical sample, mp 212°-214° C.

Analysis: Calculated for C₂₁ H₂₀ F₃ N₃ O.C₄ H₄ O₄ : 59.64%C, 4.80%H,8.35%N. Found: 59.57%C, 4.86%H, 8.41%N.

EXAMPLE 49 1-(4-Chlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 mlof 4-chlorobenzoyl chloride was heated at 100° C. in a steam bath for 4hrs. After cooling to ambient temperature, ether was added and the saltwas collected. The salt was converted into its free base by means ofammonium hydroxide solution and extractive isolation withdichloromethane. The base was dissolved in 150 ml of hot ethanol and 1.6g of fumaric acid was added. Ether (200 ml) was added to the solutionand the fumarate salt was collected. Two recrystallizations from ethanolyielded 3.5 g (54%) of product, mp 216°-218° C.

Analysis: Calculated for C₂₀ H₂₀ ClN₃ O.C₄ H₄ O₄ : 61.34%C, 5.15%H,8.94%N. Found: 61.42%C, 5.18%H, 9.00%N.

EXAMPLE 50 6-Chloro-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred solution, under nitrogen, of 13.0 g of4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester in150 ml of tetrahydrofuran was added, dropwise, 48 ml of a 1M solution oflithium aluminum hydride (0.048 mole) in tetrahydrofuran. The solutionwas stirred under reflux for 1 hr. The reaction mixture was cooled in anice-bath and water was added slowly. The reaction mixture was filtered,the filter cake washed with tetrahydrofuran and methanol, and thefiltrate was concentrated. Recrystallization of the residue fromethanol-water yielded 7.6 g (69%) of product, mp 211°-213° C.

Analysis: Calculated for C₁₃ H₁₆ ClN₃ : 62.52%C, 6.46%H, 16.83%N. Found:62.73%C, 6.61%H, 16.96%N.

EXAMPLE 51 3-(1-Ethyl-4-piperidinyl)-6-fluoro-1H-indazole

To a stirred suspension, under nitrogen, of 14.0 g of3-(1-acetyl-4-piperidinyl)-6-fluoro-1H-indazole in 180 ml oftetrahydrofuran was added, dropwise, 55 ml of a 1M solution of lithiumaluminum hydride in tetrahydrofuran. The reaction mixture was stirredunder reflux for 1 hr and then stirred at ambient temperature for 15hrs. The reaction mixture was cooled in an ice-salt bath and water wasadded slowly. The reaction mixture was filtered. The filter cake waswashed with tetrahydrofuran and the filtrate was concentrated.Recrystallization of the residue from toluene afforded 9.0 g (68%) ofproduct. Recrystallization of a 3.0 g sample from toluene yielded theanalytical sample, mp 175°-178° C.

Analysis: Calculated for C₁₄ H₁₈ FN₃ : 67.99%C, 7.34%H, 16.99%N. Found:68.07%C, 7.33%H, 17.11%N.

EXAMPLE 52 6-Chloro-3-(4-piperidinyl)-1H-indazole

A solution of 18.0 g of 1-acetyl-4-(4-chloro-2-fluorobenzoyl)piperidine,130 ml of n-butanol and 51 ml of hydrazine monohydrate was stirred underreflux for 48 hrs. Most of the n-butanol was evaporated in vacuo and theresidue was diluted with water. The aqueous mixture was extracted withethyl acetate, and the extract was washed with water, dried overanhydrous magnesium sulfate and concentrated. The residue wasrecrystallized from acetonitrile to yield 3.0 g (20%) of product. Thisproduct was combined with a 1.3 g sample from another experiment and thecombined samples (4.3 g) were recrystallized from acetonitrile to yieldthe analytical sample, mp 174°-176° C.

Analysis: Calculated for C₁₂ H₁₄ ClN₃ : 61.14%C, 5.99%H, 17.88%N. Found:61.02%C, 5.94%H, 17.94%N.

EXAMPLE 53 3-(4-piperidinyl)-1H-indazole

A solution of 4.7 g of 4-(1H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester and 80% of acetic acid was heated under reflux for 48 hrs.The reaction mixture was cooled and poured into water. The aqueous phasewas extracted with ether and then made basic by the slow addition of a50% aqueous sodium hydroxide solution. A solid separated from thesolution. The solid was collected and dried. Recrystallization fromethanol yielded 1.7 g (46%) of product. Concentration of the motherliquors from this and another experiment gave additional product, mp213°-215° C.

Analysis: Calculated for C₁₂ H₁₅ N₃ : 71.61%C, 7.51%H, 20.88%N. Found:70.89%C, 7.48%H, 20.74%N.

EXAMPLE 54 6-Bromo-1-methyl-3-(4-piperidinyl)-1H-indazole hydrochloride

A solution of 3.3 g of 4-(4-bromo-2-fluorobenzoyl)-1-acetylpyridine, 1.1g of (0.013 mole) of methylhydrazine and 30 ml of n-butanol was heatedunder reflux for 16 hrs. The reaction mixture was concentrated in vacuoand the residue was diluted with water. The aqueous suspension was madebasic with ammonium hydroxide solution and extracted withdichloromethane. The extract was washed with water, dried over anhydrouspotassium carbonate and the solvent was concentrated to give3-(1-acetyl-4-piperidinyl)-6-bromo-1H-indazole, as an oil.

A solution of 3.0 g of 3-(1-acetyl-4-piperidinyl)-6-bromo-1H-indazoleand 30 ml of 6N hydrochloric acid was heated under reflux for 4 hrs. Thereaction mixture was cooled in an ice-bath, stirred and 50% aqueoussodium hydroxide solution was added dropwise until the reaction mixturewas basic. The aqueous mixture was extracted with ether. The etherextracts were washed with water, dried over anhydrous magnesium sulfateand the solvent was concentrated to yield 1.6 g (62%) of product, as anoil. The products from three experiments were combined and converted tothe hydrochloride salt with ethereal hydrogen chloride. The salt wasrecrystallized twice from ethanol-ether and then once fromtrichloromethane-ether to yield the analytical sample, mp 238°-240° C.

Analysis: Calculated for C₁₃ H₁₆ BrN₃.HCl: 47.22%C, 5.18%H, 12.71%N.Found: 46.96%C, 5.12%H, 12.66%N.

EXAMPLE 55 3-(1-Acetyl-4-piperidinyl)-6-fluoro-1H-indazole

A solution of 15.0 g of 4-(2,4-difluorobenzoyl)-1-acetylpiperidine, 6.9g of hydrazine hydrate and 140 ml of ethanol was heated under reflux for4 hrs. The ethanol was removed in vacuo to give a solid. The solid wastriturated with water, filtered and dried to yield 12.5 g (64%) of1-acetyl-4-(2,4-difluorobenzoyl)piperidine hydrazone, mp 139°-142° C.

A mixture of 12.1 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidinehydrazone, 11.8 g of potassium carbonate and 120 ml of dimethylformamidewas stirred and heated at 120° C. for 16 hrs. The reaction mixture waspoured into water and the aqueous solution was extracted with ethylacetate. The extract was washed with water, dried over anhydrousmagnesium sulfate and the solvent concentrated to give a solid.Recrystallization of the solid from ethyl acetate (twice) yielded 4.1 g(42% with concentration of mother liquor) of product, mp 162°-164° C.

Analysis: Calculated for C₁₄ H₁₆ FN₃ O: 64.35%C, 6.17%H, 16.88%N. Found:64.10%C, 6.31%H, 15.89%N.

EXAMPLE 56 3-(1-Acetyl-4-piperidinyl)-6-chloro-1H-indazole

A mixture of 19.6 g of 1-acetyl-4-(2-fluoro-4-chlorobenzoyl)piperidinehydrazone, 18.2 g of potassium carbonate and 200 ml of dimethylformamidewas stirred, under nitrogen, at 120° C. for 16 hrs. After cooling toambient temperature, the reaction mixture was poured into water and theaqueous mixture was extracted with ethyl acetate. The extract was washedwith water, dried over anhydrous magnesium sulfate and concentrated toan oil. Upon standing, a solid formed. The solid was triturated withethyl acetate to yield 3.8 g (21%) of product. Recrystallization fromacetonitrile gave the analytical sample, mp 172°-174° C.

Analysis: Calculated for C₁₄ H₁₆ ClN₃ O: 60.54%C, 5.81%H, 15.13%N.Found: 60.55%C, 5.83%H, 15.33%N.

EXAMPLE 57 4-(6-Chloro-1H-indazol-3-yl)piperidine-1-carboxylic acidmethyl ester

To a stirred suspension of 5.8 g of6-chloro-3-(4-piperidinyl)-1H-indazole, 4.6 g of sodium bicarbonate andtrichloromethane (25 m)-tetrahydrofuran (25 ml) was added, dropwise, 5.2g of methyl chloroformate. The reaction mixture was stirred at ambienttemperature for 16 hrs and then poured into water. The organic layer wascollected, washed with water, dried over anhydrous potassium carbonateand the solvent concentrated to give4-(6-chloro-1-methyoxycarbonyl-1H-indazol-3-yl)piperidine-1-carboxylicacid methyl ester, as an oil. The oil was dissolved in 50 ml of methanoland 1.5 ml of a 25% sodium methoxide-methanol solution was added. Thereaction mixture was stirred at ambient temperature for 0.5 hrs, pouredinto water and the aqueous mixture extracted with dichloromethane. Thedichloromethane extract was washed with water, dried over anhydrousmagnesium sulfate and the solvent evaporated to an oil. The oil wastriturated with hexane. Recrystallization from toluene-hexane (twice)yielded 3.5 g (47%) of product, mp 132°-134° C.

Analysis: Calculated for C₁₄ H₁₆ ClN₃ O₂ : 57.24%C, 5.49%H, 14.30%N.Found: 57.22%C, 5.46%H, 14.33%N.

EXAMPLE 58 1-(4-Pyridinyl)-3-(1-methyl-4-piperidinyl)-1H-indazolesesquifumarate

To a stirred suspension of 1.72 g of a 50% oil dispersion of sodiumhydride, under nitrogen, in 30 ml of dimethylformamide was added,dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 25 ml ofhot dimethylformamide. After stirring at ambient temperature for 45mins, 2.3 g of 4-chloropyridine hydrochloride was added portionwise. Thereaction mixture was stirred at ambient temperature for 16 hrs and thenheated under reflux for 12 hrs. The reaction mixture was cooled toambient temperature and 0.43 g of a 50% oil dispersion of sodium hydridewas added followed by 0.6 g of 4-chloropyridine. The reaction mixturewas then heated under reflux for an additional 4 hrs, cooled to ambienttemperature and poured into water. The aqueous mixture was extractedwith ethyl acetate. The ethyl acetate extract was washed with water,dried over anhydrous magnesium sulfate and the solvent was removed invacuo. The residue was purified in two runs by flash chromatography(silica gel, 150×50 mm), eluting with ethyl acetate-diethylamine (9:1).Similar fractions were combined and evaporated. The residue wasconverted to the fumarate salt by dissolution in ethanol (25 ml)-ether(175 ml) and by adding 1.9 g of fumaric acid. Recrystallization fromdimethylformamide yielded 3.2 g (46%) of product, mp 205°-207° C.

Analysis: Calculated for C₁₈ H₂₀ N₄.1.5C₄ H₄ O₄ : 61.79%C, 5.62%H,12.01%N. Found: 61.50%C, 5.78%H, 12.18%N.

EXAMPLE 59 1-(2-Pyridinyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

To a stirred suspension, under nitrogen, of 0.86 g of a 50% oildispersion of sodium hydride in 20 ml of dimethylformamide was added,dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in25 ml of hot dimethylformamide. The reaction mixture was stirred atambient temperature for 1 hr and then 1.5 g of 2-fluoropyridine wasadded. The temperature was raised to 95°-100° C. and held there for 6hrs. The reaction mixture was allowed to cool and was then poured intowater. A solid separated from the solution. The solid was collected anddried to yield 3.5 g (79.8%) of product, mp 123°-125° C., as the freebase. The fumarate salt was prepared by dissolving the product in hotethanol, adding 2.7 g of fumaric acid and heating the mixture on thesteam bath. After a few mins, the fumarate salt precipitated from thesolution. The mixture was allowed to stand overnight at ambienttemperature and the salt was collected. Two recrystallizations frommethanol-ether yielded 2.8 g (46%) of product, mp 203°-205° C.

Analysis: Calculated for C₁₈ H₂₀ N₄.C₄ H₄ O₄ : 64.69%C, 5.92%H, 13.72%N.Found: 64.69%C, 6.00%H, 13.77%N.

EXAMPLE 60 1-(3-Hydroxy-1-propyl)-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred suspension of 0.35 g of a 50-55% oil dispersion of lithiumaluminum hydride in 50 ml of tetrahydrofuran was added, dropwise, undernitrogen, 2.4 g of1-(3-ethoxycarbonyl-1-ethyl)-3-(1-methyl-4-piperidinyl)-1H-indazole in25 ml of tetrahydrofuran. The reaction mixture was stirred under refluxfor 1.5 hrs, cooled in an ice-salt bath, and water was added dropwise.The reaction mixture was filtered. The filter cake was washed withtetrahydrofuran and the filtrate concentrated in vacuo to give an oil.The oil was taken up in dichloromethane. The dichloromethane was washedwith water, dried over anhydrous magnesium sulfate and the solventremoved in vacuo to yield 1.7 g (81%) of product. The product wascombined with that from another experiment (total 3.2 g) andrecrystallized twice from ethyl acetate-hexane to yield the analyticalsample, mp 96°-98° C.

Analysis: Calculated for C₁₆ H₂₃ N₃ O: 70.29%C, 8.48%H, 15.37%N. Found:70.53%C, 8.34%H, 15.47%N.

EXAMPLE 61 4-(4-Bromo-2-fluorobenzoyl)-1-acetylpiperidine

To a stirred suspension of 21.1 g of aluminum chloride and 63 ml of3-fluorobromobenzene was added, portionwise, 16.0 g of1-acetylisonipecotoyl chloride. The reaction mixture was stirred underreflux for 4 hrs. Most of the supernatant 3-fluorobromobenzene wasdecanted and ice water was added. The aqueous mixture was extracted withdichloromethane and the extract was washed with water, dried overanhydrous magnesium sulfate and the solvent concentrated to give an oil.The oil was triturated with ether and a solid separated out.Recrystallization of the solid from cyclohexane gave 4.9 g (19%) ofproduct. Recrystallization from cyclohexane yielded the analyticalsample, mp 111°-113° C.

Analysis: Calculated for C₁₄ H₁₅ BrFNO₂ : 51.23%C, 4.61%H, 4.24%N.Found: 51.40%C, 4.61%H, 3.92%N.

EXAMPLE 621-(ethoxycarbonyl-ethyl)-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred suspension, under nitrogen, of 1.7 g of a 50% oildispersion of sodium hydride in 75 ml of dimethylformamide was added,dropwise, 6.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 30 ml ofhot dimethylformamide. Upon completion of the addition, the reactionmixture was stirred at ambient temperature for 1 hr and a solution of6.5 g of ethyl 3-bromopropionate was added dropwise. The reactionmixture was stirred at ambient temperature for 3 hrs and then pouredinto water. The aqueous mixture was extracted with ethyl acetate and theextracts were washed with water, dried over anhydrous magnesium sulfateand filtered. Evaporation of the filtrate under vacuum gave 6.5 g(70.8%) of product, as an oil.

EXAMPLE 63 6-Bromo-3-(4-piperidinyl)-1H-indazole

A mixture of 9.6 g of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine and50 ml of hydrazine hydrate was stirred in an autoclave at 135°-140° C.for 20 hr. The reaction mixture was quenched with water and the solidwas collected. The solid was recrystallized from acetonitrile (charcoal)to yield 2.6 g (32%) of product, mp 163°-165° C.

Analysis: Calculated for C₁₂ H₁₄ BrN₃ : 51.44%C, 5.04%H, 15.00%N. Found:51.35%C, 5.05%H, 15.23%N.

EXAMPLE 64 3-(1-Methyl-4-piperidinyl)-1-methyl-1H-indazole hydrochloridemonohydrate

A mixture of 10.0 g of 4-(2-fluorobenzoyl)-1-methylpiperidine and 2.70 gof methyl hydrazine in 250 ml of n-butanol was heated under reflux for16 hrs. The reaction mixture was then poured into water and extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate and concentrated to an oil. An ethereal hydrogen chloridesolution was added to the oil. The salt was recrystallized twice fromethanol-ether to yield 3.1 g (26%) of product, mp 198°-200° C.

Analysis: Calculated for C₁₄ H₁₉ N₃.HCl.H₂ O: 59.25%C, 7.81%H, 14.81%N.Found: 59.81%C, 7.67%H, 14.81%N.

EXAMPLE 653-(1-Methyl-4-piperidinyl)-1-[3-(trifluoromethyl)phenyl]-1H-indazole

To a stirred suspension of 4.9 g of a 50% oil dispersion of sodiumhydride in 60 ml of dimethylformamide was added dropwise a solution a10.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 80 ml of hotdimethylformamide. The reaction mixture was stirred for 1 hr and then15.2 g of 3-fluorobenzotrifluoride was added. The reaction was heated at90° C. for 22 hrs, cooled and poured into water. The aqueous mixture wasextracted with ether. The ethereal extracts were dried over anhydrousmagnesium sulfate and concentrated to give an oil. The oil was flashchromatographed (silica gel, diethylamine-ethyl acetate (1:9)).Evaporation of the appropriate fractions followed by recrystallizationtwice from hexane yielded 2.96 g (18%) of product, mp 103°-105° C.

Analysis: Calculated for C₂₀ H₂₀ F₃ N₃ : 66.84%C, 5.61%H, 11.69%N.Found: 66.74%C, 5.64%H, 11.76%N.

EXAMPLE 66 3-(1-Methyl-4-piperidinyl)-1-phenyl-1H-indazole hydrochloride

A mixture of 14.6 g of 4-(2-fluorobenzoyl)-1-methylpiperidine, 12.0 g ofphenylhydrazine hydrochloride and 16.0 g of sodium acetate in 280 ml ofn-butanol was heated under reflux for 3.5 hrs. The reaction mixture wascooled, filtered and concentrated. The residue was washed with ether toyield 17 g (83%) of 4-(2-fluorobenzoyl)-1-methylpiperidinephenylhydrazone, mp 131°-134° C.

To a solution of 10.0 g of 4-(2-fluorobenzoyl)-1-methylpiperidinephenylhydrazone in 110 ml of dimethylformamide was added 2.42 g of a 50%oil dispersion of sodium hydride. The reaction mixture was stirred at80° C. for 2 hrs, cooled and poured into water. The aqueous mixture wasextracted with ethyl acetate. The extracts were dried over anhydrousmagnesium sulfate and concentrated to an oil. The oil was dissolved inether and a solution of hydrogen chloride gas in ether was added. Thesalt was washed with ether and recrystallized twice from acetonitrile toyield 3.66 g (35%) of product, mp 277°-279° C.

Analysis: Calculated for C₁₉ H₂₁ N₃.HCl: 69.61%C, 6.76%H, 12.82%N.Found: 69.47%C, 6.77%H, 12.90%N.

EXAMPLE 67 1-(4-Fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolehydrochloride

A stirred mixture of 21.8 g of 4-(2-fluorobenzoyl)-1-methylpiperidine,20.25 g of 4-fluorophenyl hydrazine hydrochloride and 25.0 g of sodiumacetate in 420 ml of n-butanol was heated under reflux for 8 hrs. Themixture was cooled, filtered, and concentrated. The residue was washedwith ether to give 7.5 g (23%) of 4-(2-fluorobenzoyl)-1-methylpiperidine4-fluorophenylhydrazone, mp 125°-126° C.

To a solution of 7.5 g of 4-(2-fluorobenzoyl)-1-methylpiperidine4-fluorophenylhydrazone in 80 ml of dimethyformamide was added 2.4 g ofa 50% oil dispersion of sodium hydride. The reaction mixture was stirredat 80° C. for 2 hrs, cooled and poured into water. The aqueous mixturewas extracted with ethyl acetate. The extracts were dried over anhydrousmagnesium sulfate and concentrated to an oil. The oil was dissolved inether and an ethereal hydrogen chloride solution was added. The salt waswashed with ether and recrystallized twice from acetonitrile to yield2.0 g of product. The product was combined with 2.1 g of a previouslyprepared sample and recrystallized from acetonitrile to give 3.0 g (19%)of product, mp 198°-199° C.

Analysis: Calculated for C₁₉ H₂₀ FN₃.HCl: 65.99%C, 6.12%H, 12.15%N.Found: 65.87%C, 6.07%H, 12.18%N.

EXAMPLE 68 6-Fluoro-1-methyl-3-(4-piperidinyl)-1H-indazole hydrochloride

A solution of 5.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, 1.2 gof methylhydrazine and 50 ml of n-butanol was heated under reflux for 16hrs. After cooling, the solvent was removed in vacuo and the residue wasdiluted with water. The aqueous mixture was made basic with ammoniumhydroxide and extracted with dichloromethane. The organic extract waswashed with water, dried over anhydrous magnesium sulfate andconcentrated to yield 5.6 g of3-(1-acetyl-4-piperidinyl)-6-fluoro-1-methyl-1H-indazole as an oil.

A solution of 16.8 g of3-(1-acetyl-4-piperidinyl)-6-fluoro-1-methyl-1H-indazole and 100 ml of6N hydrochloric acid was heated under reflux for 4 hrs. The solution wascooled in an ice bath, 50% aqueous sodium hydroxide was added, dropwise,with stirring and the mixture was extracted with ethyl acetate.Concentration of the organic extract gave an oil. The oil was dissolvedin ethyl acetate and a saturated solution of ethyl acetate-hydrogenchloride was added. The salt was recrystallized twice fromtrichloromethane-ether and then from isopropanol (charcoal) to yield 3.0g (21%) of product, mp 256°-258° C.

Analysis: Calculated for C₁₃ H₁₆ FN₃.HCl: 57.88%C, 5.98%H, 15.58%N.Found: 57.58%C, 6.34%H, 15.48%N.

EXAMPLE 69 4-(1H-Indazol-3-yl)piperidine-1-carboximidic acid methylester

To a stirred suspension of 4-(1H-indazol-3-yl)piperidine-1-carbonitrile(7.9 g, 0.024 mole) in methanol (15 ml) was added 4.9 ml of 25% solutionof sodium methoxide in methanol. The solution was stirred at ambienttemperature for 16 hours, made neutral to pH paper with glacial aceticacid, and extracted with ether. The aqueous solution was made basic withconcentrated NH₄ OH, and extracted thrice with CH₂ Cl₂ (35 ml). Theorganic extracts were combined, washed (H₂ O), dried (MgSO₄) and thesolvent removed in vacuo to yield 6.6 g of an oil. The oil wastriturated with hexane and the resultant solid collected (5.4 g).Recrystallization from CH₃ CN (twice) yielded 3.5 g (56.8%) of4-(1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester having amelting point of 153°-155° C.

Analysis: Calculated for C₁₄ H₁₈ N₄ O: 65.09%C, 7.02%H, 21.69%N. Found:65.27%C, 6.96%H, 21.74%N.

EXAMPLE 70 a. 4-(6-Fluoro-1H-indazol-3-yl)piperidine-1-carbonitrile

To a mixture of NaHCO₃ (2.3 g., 1.027 mol), BrCN (1,5 g, 0.0141 mol.,97%) and dimethyl sulfoxide (DMSO) [20 ml.], was added dropwise6-fluoro-3-(4-piperidinyl)-1H-indazole (3.0 g., 0.014 mol) dissolved in30 ml. of warm DMSO. After two hours at ambient temperature the reactionmixture was poured into water and the resultant solid was collected,dried and yielded 3.6 g. of4-(6-fluoro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 143°-145° C.

b. 4-(6-fluoro-1H-indazol-3-yl)piperidine-1-carboximidic acid methylester

A solution of 4-(6-fluoro-1H-indazol-3-yl)piperidine-1-carbonitrile (3.0g. 0.012 mol) of Example 70a, methanol (35 ml) and 25% sodium methoxidein methanol (2.5 ml) was stirred at ambient temperature for 16 hours.Most of the methanol was removed in vacuo and the residue diluted withwater. The aqueous mixture was extracted with CH₂ Cl₂. The extract waswashed (H₂ O), dried (Na₂ SO₄) and the solvent evaporated to yield 3.0 gof a solid. The material was recrystallized from toluene to give 2.4 g(72%) of 4-(6-fluoro-1H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester, m.p. 162°-164° C.

Analysis: Calculated for C₁₄ H₁₇ FN₄ O: 60.85%C, 6.20%H, 20.28%N. Found:61.39%C, 6.28%H, 20.09%N.

EXAMPLE 714-(6-Fluoro-1-methyl-1H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester

To a stirred mixture of cyanogen bromide (2.2 g, 0.021 mol), sodiumbicarbonate (3.5 g) and dimethyl sulfoxide (DMSO) (40 ml) was added6-fluoro-1-methyl-3-(4-piperidinyl)-1H-indazole (5.0 g, 0.021 mol) freebase of Example 68 in DMSO (50 ml). The reaction was stirred at ambienttemperature for 2 hours and then poured into water. The cyanamideseparated from solution and was collected to yield 4.9 g of a solid.Recrystallization from ethylacetate-hexane yielded 3.6 g (66%) of4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine-1-carbonitrile,, mp.133°-136° C.

To a stirred mixture of4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine-1-carbonitrile (3.4 g,0.013 mole) and methanol (40 ml) was added a 25% sodiummethoxide-methanol solution (2.5 ml). The mixture was warmed briefly toeffect solution and was then stirred at ambient temperature for 16hours. The methanol was concentrated and the residue was diluted withwater. The resulting precipitate was collected to yield 3.8 g of theproduct as a solid. The material was recrystallized from toluene-hexaneto yield 3.0 g of4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester, mp 132°-135° C.

Analysis: Calculated for C₁₅ H₁₉ FN₄ O: 62.05%C, 6.59%H, 19.30%N. Found:61.95%C, 6.54%H, 19.13%N.

EXAMPLE 72 4-(6-Chloro-3H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester

To a stirred mixture of cyanogen bromide (1.8 g, 0.017 mol), sodiumbicarbonate (2.80 g) and dimethyl sulfoxide (DMSO) (40 ml) was addeddropwise 6-chloro-3-(4-piperidinyl)-1H-indazole (4.0 g, 0.017 mol) ofExample 52 dissolved in DMSO (50 ml). The reaction was stirred atambient temperature for 1 hour and poured into water. The resultingsolid was collected, dried and weighed 4.0 g. Recrystallization fromtoluene-hexane afforded 3.1 g (70%) of4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 180°-188° C.To a stirred mixture of4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile (3.0 g., 0.015mol) in methanol (30 ml) was added a solution of 25% sodium methoxide inmethanol (2.5 ml). The reaction was warmed on a steam bath to effectsolution and then stirred at ambient temperature for 16 hours. Most ofthe methanol was removed in vacuo and the residue was diluted withwater. An initial oil solidified and 3.5 g of a solid was collected.This was recrystallized from methanol-water to yield 2.9 g (66%) of4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester,mp 173°-175° C.

Analysis: Calculated for C₁₄ H₁₉ ClN₄ O: 57.43%C, 5.85%H, 19.14%N.Found: 57.44%C, 5.87%H, 19.34%N.

EXAMPLE 73 4-(1-Phenyl-1H-indazole-3-yl)piperidine-1-carbonitrile

To a mixture of cyanogen bromide (5.76 g, 0.054 moles) and K₂ CO₃ (8.82g, 0.064 moles) in dimethylsulfoxide (110 ml) was added3-(1-methyl-4-piperidinyl)-1-phenyl-1H-indazole (14.8 g, 0.051 moles) ofExample 66 in dimethylsulfoxide (DMSO) (15 ml). The reaction was stirredat ambient temperature for 16 hours and then poured into water andextracted with ether. A precipitate formed in the ether which wascollected and then the ether was concentrated to yield additionalproduct. The crude product (11.5 g) was recrystallized three times fromisopropyl alcohol which yielded 6.75 g (37%) of4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 124°-125° C.

Analysis: Calculated for C₁₉ H₁₈ N₄ : 75.47%C, 6.00%H, 18.52%N. Found:75.59%C, 6.07%H, 18.61%N.

EXAMPLE 744-[1-(2-Fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile

To a stirred mixture of cyanogen bromide (15.5 g, 0.146 moles) andpotassium carbonate (23.7 g, 0.167 moles) in dimethylsulfoxide (DMSO)[300 ml] was added dropwise a solution of1-(2-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole, the free baseof example 36, (42.0 g, 0.137 moles) in dimethylsulfoxide (40 ml). Thereaction temperature rose to 36° C. and the mixture was stirred atambient temperature for 2.5 days. The reaction mixture was then pouredinto H₂ O and the product extracted with ether. The ether was dried(MgSO₄) and concentrated which left 40 g of a solid. The product wasrecrystallized 5 times from isopropyl alcohol which yielded 13.6 g (31%)of 4-[1-(2-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, m.p.119°-121° C.

Analysis: Calculated for C₁₉ H₁₇ FN₄ : 71.33%C, 5.35%H, 17.49%N. Found:71.13%C, 5.62%H, 17.43%N.

EXAMPLE 75N-Phenyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide

To a solution of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole thefree base of Example 98 (1.8 g, 0.0061 mol) in toluene (25 ml) was addedphenyl isocyanate (0.8 g, 0.0067 mol), and the solution was warmed at100° C. (steam bath) for 15 minutes. Upon cooling to ambienttemperature, a solid precipitated from solution. Cyclohexane was added,and the product was collected yielding 2.1 g (83%) of a solid, mp163°-165° C. This material was combined with a 2.5 g sample from anotherreaction, and recrystallization from toluene-cyclohexane and then fromtoluene yielded 3.4 g ofN-phenyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide,mp 163°-165° C.

Analysis: Calculated for C₂₅ H₂₃ FN₄ O: 72.44%C, 5.59%H, 13.52%N. Found:72.40%C, 5.62%H, 13.50%N.

EXAMPLE 76N-Phenyl-4-[1-(2-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxamide

A stirred mixture of4-[1-(2-fluorophenyl)-1H-indazole-3-yl]piperidine-1-carbonitrile ofExample 74 (32.7 g, 0.102 moles) and 25% H₂ SO₄ (300 ml) was refluxedfor 20 hours. The mixture was cooled, poured into water and basifiedwith 25% NaOH solution. The product was extracted with dichloromethane,dried (MgSO₄) and concentrated which yielded 28 g of an oil. The oil wastriturated with acetone to produce 14 g (47%) of product as a solid. Toa suspension of the solid (4.0 g, 0.0136 moles) in toluene (100 ml) wasadded dropwise phenyl isocyanate (4.4 ml, 0.041 moles). The mixture wasthen stirred at reflux for 12 hours. Concentration of the reactionmixture yielded 6.8 g of an oil. The oil was purified using highpressure liquid chromatography (silica gel, 40% ethyl acetate/hexane)which yielded 2.65 g of a solid. The solid was recrystallized fromtoluene-hexane which yielded 2.25 g (40%) ofN-phenyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide,m.p. 166°-168° C.

Analysis: Calculated for C₂₅ H₂₃ FN₄ O: 72.455C, 5.59%H, 13.52%N. Found:72.60%C, 5.69%H, 13.24%N.

EXAMPLE 774-[1-[4-(Trifluoromethyl)phenyl]-1H-indazol-3-yl]-1-piperidinecarboxamide hydrobromide

A mixture of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrileof Example 101 (5.0 g, 0.0135 moles) and NaOCH₃ (3.1 ml of a 25%methanol solution, 0.0136 moles) in methanol (30 ml) was warmed toeffect solution and then stirred at ambient temperature for 3 hours. Themixture was poured into H₂ O, extracted with CHCl₃, and dried withMgSO₄. Concentration produced an oil which was triturated with hexane toyield 3.93 g (72%) of an imidate as a solid, mp 96°-98° C. A mixture ofthe imidate (3.9 g, 0.0097 moles) and a HBr solution (40 ml of a 48%solution) was heated at 90° C. for 17 hours. The mixture was cooled,causing the product to precipitate from the solution. The product wascollected, washed with ether, and then recrystallized from isopropylalcohol-ether to yield 2.1 g (46%) of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamidehydrobromide, mp 130°-132°.

Analysis: Calculated for C₂₀ H₁₉ F₃ N₄ O.HBr: 51.19%C, 4.30%H, 11.94%N.Found: 51.47%C, 4.31%H, 11.84%N.

EXAMPLE 78N-Phenyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3yl]piperidine-1-carboxamide

A stirred mixture of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3yl]piperidine-1-carbonitrileof Example 77 (15 g, 0.041 moles) and 25% H₂ SO₄ (100 ml) was refluxedfor 20 hours. The mixture was cooled, poured into H₂ O, and basifiedwith a 25% NaOH solution. The product was extracted (dichloromethane),dried (MgSO₄), and concentrated to yield 13 g (93%) of1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil.To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene(60 ml) was added phenyl isocyanate (1.38 ml, 0.013 moles). The reactiontemperature rose to 35° C. and the product precipitated from thesolution. The product was collected and recrystallized twice fromtoluene to yield 3.57 g (66%) ofN-phenyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide,m.p. 190°-192° C.

Analysis: Calculated for C₂₆ H₂₃ F₃ N₄ O: 67.23%C, 4.99%H, 12.06%N.Found: 67.16%C, 5.05%H, 11.96%N.

EXAMPLE 79N-Methyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide

To a solution of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole ofExample 98 (4.0 g, 0.014 mol) in toluene (50 ml) was added methylisocyanate (0.94 g. 0.016 mol). The reaction was warmed on a steam bathfor 15 minutes, and upon cooling to ambient temperature a solidprecipitated. Hexane was added and the solid was filtered to yield 4.0 gof a urea. The compound was recrystallized twice from toluene to yield3.4 g (69%) ofN-methyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide,mp 163°-165° C.

Analysis: Calculated for C₂₀ H₂₁ FN₄ O: 68.18%C, 6.00%H, 15.90%N. Found:68.33%C, 6.00%H, 15.46%N.

EXAMPLE 80N-Phenyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbothioamide

A solution of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole free baseof Example 98 (3.5 g, 0.012 mol) and phenyl isothiocyanate (2.0g, 0.015mol) in toluene (20 ml) was heated on a steam bath for 15 minutes. Anadditional 0.2 ml of phenyl isothiocyanate was added and the solutionwas heated again for 15 minutes. The reaction was then stirred atambient temperature for 16 hours, and a solid precipitated fromsolution. Hexane was added to the mixture, and the solid was collectedto yield 4.5 g of a thiourea. Two recrystallizations from tolueneyielded 3.2 (64%) ofN-phenyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbothioamide,mp 151°-153° C.

Analysis: Calculated for C₂₅ H₂₃ FN₄ S: 69.75%C, 5.38%H, 13.02%N. Found:69.87%C, 5.34%H, 12.91%N.

EXAMPLE 81N-Methyl-4-[1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl]piperidine-1-carboxamide

A stirred mixture of4-[1-(4-(trifluoromethyl)phenyl-1H-indazol-3-yl]piperidine-1-carbonitrileof Example 101 (15 g, 0.041 moles) and 25% H₂ SO₄ (100 ml) was refluxedfor 20 hours. The mixture was cooled, poured into H₂ O and basified witha 25% NaOH solution. The product was extracted (dichloromethane), dried(MgSO₄), and concentrated to yield 13 g (93%) of1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil.To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene(60 ml) was added methyl isocyanate (0.75 ml., 0.013 moles). Thetemperature of the reaction mixture rose to 35° C. following theaddition. The mixture was stirred for 2 hours at ambient temperature andthen concentrated to yield 4.6 g of a solid. The product was purified byhigh pressure liquid chromatography (3.5% methanol-CHCl₃ ; silica gel)and then recrystallized three times from toluene-hexane to yield 2.93 g(63%) ofN-methyl-4-[1-(4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide,m.p.: 150°-152° C.

Analysis: Calculated for C₂₁ H₂₁ F₃ N₄ O: 62.68%C, 5.26%H, 13.92%N.Found: 62.91%C, 5.44%H, 13.84%N.

EXAMPLE 82N-Methyl-4-[1-(4-fluorophenyl)-1H-indazol-3yl]piperidine-1-carboxamide

A stirred mixture of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 102 (30 g, 0.094 moles) and 25% H₂ SO₄ (225 ml) was refluxed for20 hours. The mixture was cooled, poured into H₂ O, and basified with a25% NaOH solution. The product was extracted (dichloromethane), dried(MgSO₄), and concentrated to yield 21 g (76%) of1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirredsuspension of the indazole (5.0 g, 0.017 moles) in toluene (90 ml) wasadded methyl isocyanate (1.1 ml, 0.019 moles). The mixture was stirredfor 16 hours at ambient temperature and then concentrated to yield 5.8 gof an oil. The oil was triturated with ether causing the product tosolidify. The product was recrystallized twice from isopropylalcohol-hexane to yield 3.44 g (58%) of N-methyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxamide, m.p. 113°-115° C.

Analysis: Calculated for C₂₀ H₂₁ FN₄ O: 68.16%C, 6.01%H, 15.90%N. Found:68.04%C, 5.95%H, 15.79%N.

EXAMPLE 83N-Methyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbothioamide

A stirred mixture of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 102 (30 g, 0.094 moles) and 25% H₂ SO₄ (225 ml) was refluxed for20 hours. The mixture was cooled, poured into H₂ O, and basified with a25% NaOH solution. The product was extracted (dichloromethane), dried(MgSO₄), and concentrated to yield 21 g (76%) of1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirredsuspension of the indazole (4.0 g, 0.0135 moles) in toluene (70 ml) wasadded dropwise methyl isothiocyanate (1.5 ml, 0.022 moles). The mixturewas stirred for 23 hours at ambient temperature during which time theproduct precipitated from the solution. The product was collected andrecrystallized twice from isopropyl alcohol to yield 2.74 g (55%) ofN-methyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbothioamide,m.p. 179°-181° C.

Analysis: for C₂₀ H₂₁ FN₄ S: 65.19%C, 5.74%H, 15.21%N. Found: 65.09%C,5.77%H, 15.11%N.

EXAMPLE 844-[1-(4-Fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxamide

A mixture of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 102 (8.0 g, 0.025 moles) and sodium methoxide (5.8 ml of a 25%methanol solution, 0.025 moles) in methanol (55 ml) was warmed to effectsolution and then stirred at ambient temperatures for 3 hours. Themixture was poured into H₂ O, extracted with CHCl₃, and dried withMgSO₄. Concentration produced 8.8 g (100%) of the imidate as an oil. Amixture of the imidate (8.8 g, 0.025 moles) and aqueous HBr (100 ml of a48% solution) was heated at 90° C. for 2 hours. The mixture was thencooled, poured into H₂ O, extracted (ethyl acetate), and dried (MgSO₄).Concentration produced an oil which was triturated with hexane to yield5.5 g of product. The product was recrystallized thrice fromtoluene-hexane and then chromatographed on the high pressure liquidchromatograph (silica gel, 5% methanol/ethyl acetate) which yielded 4.7g of an oil. Recrystallization from toluene followed byrecrystallization from isopropyl alcohol yielded 2.70 g (32%) of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxamide, m.p.145°-147° C.

Analysis: Calculated for C₁₉ H₁₉ FN₄ O: 67.44%C, 5.66%H, 16.56%N. Found:67.56%C, 5.88%H, 16.55%N.

EXAMPLE 854-[1-[4-(Trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboximidicacid methyl ester

A mixture of4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]-piperidine-1-carbonitrileof Example 101 (20.0 g, 0.054 moles) and sodium methoxide (12.4 ml of25% sodium methoxide in methanol 0.054 moles) in methanol (120 ml) waswarmed to effect solution and then stirred at ambient temperature for 3hours. The mixture was poured into H₂ O, extracted (CHCl₃), dried(MgSO₄), and concentrated to yield an oil. The oil was triturated withhexane which produced 19 g of a solid. The solid was recrystallizedtwice from toluene-hexane which yielded 14.2 g (65%) of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboximidicacid methyl ester, m.p. 113°-115° C.

Analysis: Calculated for C₂₁ H₂₁ F₃ N₄ O: 62.68%C, 5.26%H, 13.92%N.Found: 62.58%C, 5.20%H, 13.91%N.

EXAMPLE 86 4-(6-Fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide

A solution of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole free baseof Example 98 (4.2 g, 0.0142 mol), nitrourea (1.5 g, 0.014 mol) andethanol (100 ml) was refluxed for 4 hours. An additional 0.75 g more ofthe nitrourea was then added and the reaction was left to stand atambient temperature for 16 hours. The ethanol was concentrated to yielda gum, which after standing in the presence of H₂ O for 4 days yielded2.8 g (58%) of a solid. This solid was combined with another sample, andthe total (6.2 g) recrystallized from ethyl acetate-diethylamine toyield 4.0 g of a solid. The solid (3.7 g) was chromatographed on apreparative high pressure liquid chromatograph (HPLC) (silica gel) usingCH₂ Cl₂ -methanol (4%) as the eluent. Evaporation of the appropriatefractions yielded 2.3 g of a solid, mp 147°-149° C. Recrystallizationfrom isopropanol yielded 1.5 g of4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide, m.p.149°-151° C.

Analysis: Calculated for C₁₉ H₁₉ FN₄ O: 67.44%C, 5.66%H, 16.56%N. Found:67.04%C, 5.88%H, 16.45%N.

EXAMPLE 87 (a) 6-chloro-1-phenyl-3-(4-piperidinyl)-1H-indazole

A mixture of 1-acetyl-4-(6-chloro-1-phenyl-1H-indazol-3-yl)piperidine(8.2 g; 0.023 mol) of Example 95(b) was stirred and refluxed with 6N HCl(75 ml) for 5 hours. The mixture was diluted with water and extractedwith ethyl acetate. The ethyl acetate was evaporated and filtered. Theaqueous solution was chilled, stirred and 50% NaOH was added dropwise.The resultant basic mixture was extracted with ethyl acetate and theorganic extract was washed and dried and then concentrated to yield anoil which solidified on standing to yield 5.7 g of6-chloro-1-phenyl-3-(4-piperidinyl)-1H-indazole.

(b) 4-(6-Chloro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide

To a stirred solution of 6-chloro-1-phenyl-3-(4-piperidinyl)-1H-indazoleof Example 87(a) (3.2 g, 0.01 mol) in acetone (100 ml) was added, all atonce, nitrourea (2.4 g, 0.023 mol). The reaction was stirred at ambienttemperature for 16 hours. A solid (1.5 g) was filtered, and the filtratewas concentrated to yield 3.4 of product as a foam. The product wascombined with 2.0 g from another run and chromatographed on apreparative high pressure liquid chromatography (HPLC) [silica gel],eluting with CH₂ Cl₂ -methanol (4%). Upon evaporation of the appropriatefractions there remained 3.4 g of a foam which upon trituration withhexane gave 3.0 g of a solid. The solid was recrystallized from ethylacetate to yield 2.1 g (33%) of4-(6-chloro-1-phenyl-1H-indazol-3-yl)piperidine-1-carboxamide, m.p.148°-158° C.

Analysis: Calculated for C₁₄ H₁₉ ClN₄ O: 64.31%C, 5.40%H, 15.80%N.Found: 64.38%C, 5.63%H, 15.86%N.

EXAMPLE 88N,N-Dimethyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol]-3-yl]piperidine-1-carboxamide

A stirred mixture of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrileof Example 101 (15 g, 0.041 moles) and 25% H₂ SO₄ (100 ml) was refluxedfor 20 hours. The mixture was cooled, poured into H₂ O, and basifiedwith a 25% NaOH solution. The product was extracted (dichloromethane),dried (MgSO₄), and concentrated to yield 13 g (93%) of1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil.To a suspension of the indazole (4.3 g, 0.012 moles) and triethylamine(3.5 ml, 0.025 moles) in toluene (50 ml) was added dimethylcarbamylchloride (1.26 ml, 0.014 moles). The reaction was stirred at ambienttemperature for 21 hours. The mixture was then poured into H₂ O,extracted (CHCl₃), dried (MgSO₄), and concentrated to yield 5.08 g of anoil. The product was purified by high pressure liquid chromatography(HPLC) [silica gel, 100% ethyl acetate] to yield 3.6 g of product as anoil which crystallized upon standing. The product was washed with hexaneand dried to yield 3.2 g (62%) ofN,N-dimethyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide,m.p. 117°-119° C.

Analysis: Calculated for C₂₂ H₂₃ F₃ N₄ O: 63.45% C, 5.57%H, 13.45%N.Found: 63.22%C, 5.72%H, 13.34%N.

EXAMPLE 891-Formyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine

A stirred mixture of4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]piperidine-1-carbonitrileof Example 101 (15 g, 0.041 moles) and 25% H₂ SO₄ (100 ml) was refluxedfor 20 hours. The mixture was cooled, poured into H₂ O, and basifiedwith a 25% NaOH solution. The product was extracted (dichloromethane),dried (MgSO₄), and concentrated which yielded 13 g (93%) of1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. Amixture of formic acid (1 ml, 0.027 moles) and acetic anhydride (2.4 ml,0.025 moles) was warmed at 55° C. for 1.5 hours. The solution was cooledto 30° C. and a suspension of the indazole (4.0 g, 0.012 moles) in ether(10 ml) was added. The mixture was stirred at ambient temperature for3.5 hours and then poured into H₂ O and basified with a 5% NaOHsolution. The product was extracted (CHCl₃), dried (MgSO₄) andconcentrated to yield 5.1 g of an oil. The oil was purified on the highpressure liquid chromatograph (silica gel, 100% ethyl acetate) to yield3.1 g (72%) of1-formyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3yl]piperidine,m.p. 109°-111° C.

Analysis: Calculated for C₂₀ H₁₈ F₃ N₃ O: 64.34%C, 4.86%H, 11.25%N.Found: 64.17%C, 4.86%H, 11.11%N.

EXAMPLE 90 1-Formyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine

A stirred mixture of4-[1-(4-fluorophenyl-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 102 (30 g, 0.094 moles) and 25% H₂ SO₄ (225 ml) was refluxed for20 hours. The mixture was cooled, poured into H₂ O, and basified with a25% NaOH solution. The product was extracted (dichloromethane), dried(MgSO₄), and concentrated to yield 21 g (76%) of1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. A mixture offormic acid (1 ml, 0.027 moles) and acetic anhydride (2.4 ml, 0.025moles) was warmed at 65° C. for 1.5 hours. The solution was cooled to30° C. and a suspension of the indazole (2.9 g, 0.010 moles) in ether(10 ml) was added. The mixture was stirred at ambient temperature for 3hours, and then poured into H₂ O and basified with a 5% NaOH solution.The product was extracted (CHCl₃), dried (MgSO₄), and concentrated toyield 3.6 g of an oil. The oil was purified on the high pressure liquidchromatograph (silica gel, 100% ethyl acetate) to yield 2.05 g (65%) of1-formyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine, m.p.128°-130° C.

Analysis: Calculated for C₁₉ H₁₈ FN₃ O: 70.57%C, 5.61%H, 12.99%N. Found:70.11%C, 5.64%H, 12.83%N.

EXAMPLE 911-Acetyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine

A stirred mixture of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrileof Example 101 (15 g. 0.041 moles) and 25% H₂ SO₄ (100 ml) was refluxedfor 20 hours. The mixture was cooled, poured into H₂ O, and basifiedwith 25% NaOH solution. The product was extracted (dichloromethane),dried (MgSO₄), and concentrated to yield 13 g (93%) of1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil.To a stirred mixture of the indazole (4.15 g. 0.012 moles) andtriethylamine (3.35 ml. 0.024 moles) in toluene (50 ml) was added acetylchloride (0.93 ml, 0.013 moles). The reaction was stirred at ambienttemperature for 2 hours and then poured into H₂ O. The product wasextracted (CHCl₃), dried (MgSO₄), and concentrated to yield 4.3 g of anoil. The product was triturated with hexane and then recrystallized fromCCl₄ -hexane twice to yield 2.80 g of product. The product was furtherpurified using high pressure liquid chromatography (silica gel, ethylacetate) to yield 2.1 g (45%) of1-acetyl-4-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p.148°-150° C.

Analysis: Calculated for C₂₁ H₂₀ F₃ N₃ O: 65.11%C, 6.20%H, 10.85%N.Found: 64.92%C, 5.22%H, 10.73%N.

EXAMPLE 92 (a) 1-Acetyl-4-(4-bromo-2-fluorobenzoyl)piperidinephenylhydrazone

A mixture of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine (16.6 g,0.051 mol), phenylhydrazine hydrochloride (16.6 g, 0.11 mol), sodiumacetate, (22.2 g) and isopropanol (250 ml) was stirred and refluxed for4 hours. The reaction stood at ambient temperature for 16 hours, andthen was filtered. The filtercake was treated with water, and theinsoluble hydrazone was collected and dried to yield 13.7 g. Theisopropanol filtrate was concentrated in vacuo to a solid, which whentriturated with ether yielded 6.1 g more of the hydrazone (total yield19.8 g; 93%). The phenylhydrazone was a mixture of the two geometricisomers. A 3.5 g sample of the compound was recrystallized fromisopropanol to yield 2.1 g of the phenylhydrazone; mp 174°-176° C.

Analysis: Calculated for C₂₀ H₂₁ BrFNO₃ : 57.42%C, 5.06%H, 10.04%N.Found: 57.14%C, 5.01%H, 9.91%N.

(b) 1-Acetyl-4-(6-bromo-1-phenyl-1H-indazol-3-yl)piperidine

To a stirred solution, under N₂, of potassium t-butoxide (2.7 g, 0.024mol) in THF (30 ml) was added, dropwise, a solution of1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine phenylhydrazone (8.4 g,0.02 mol) of Example 92 (a) in THF (60 ml). After the addition wascomplete, the reaction was stirred at ambient temperature for 2 hours.The reaction was poured into H₂ O, and the aqueous mixture was extractedwith ethyl acetate. The extract was washed (H₂ O), dried (MgSO₄) and thesolvent concentrated to yield a foam. The foam was triturated with H₂ Oto yield 7.0 g of a solid, m.p. 86°-89° C. Subsequent trituration ofthis solid with refluxing isopropyl ether yielded 6.2 g of a solid; m.p.132°-134° C. The solid was recrystallized twice from ethyl acetate toyield 2.4 g (30%) of1-acetyl-4-(6-bromo-1-phenyl-1H-indazol-3-yl)piperidine, mp 136°-138°.

Analysis: Calculated for C₂₀ H₂₀ BrN₃ O: 60.31%C, 5.06%H, 10.55%N.Found: 60.22%C, 5.03%H, 10.47%N.

EXAMPLE 93 1-Acetyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine

A stirred mixture of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 102 (30 g, 0.094 moles) and 25% H₂ SO₄ (225 ml) was refluxed for20 hours. The mixture was cooled, poured into H₂ O, and basified with a25% NaOH solution. The product was extracted (dichloromethane), dried(MgSO₄), and concentrated which yielded 21 g (76%) of1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil.

To a stirred suspension of the indazole (3.5 g, 0.012 moles) andtriethylamine (3.3 ml, 0.024 moles) in toluene (50 ml) was added acetylchloride (0.92 ml, 0.013 moles). The solution was stirred for 2 hours atambient temperature and then poured into H₂ O. The product was extracted(chloroform), dried (MgSO₄), and concentrated to yield 4.4 g of an oil.The product was purified by high pressure liquid chromatography (silicagel, 100% ethyl acetate) and then triturated with hexane to yield 3.0 gof the product as a solid. The product was recrystallized once fromtoluene-hexane which produced 2.5 g (66%) of1-acetyl-4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine, m.p. 99°-101°C.

Analysis: Calculated for C₂₀ H₂₀ FN₃ O: 71.20%C, 5.97%H, 12.45%N. Found:71.26%C, 6.15%H, 12.43%N.

EXAMPLE 94 1-Acetyl-4-(6-methylthio-1-phenyl-1H-indazol-3-yl)piperidine

A mixture of 1-acetyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine(6.8 g, 0.02 mol) of Example 39 hexamethylphosphoric triamide (70 ml)and sodium methylthiolate (2.2 g, 0.030 mol) was stirred, under nitrogenat 120° C. for 2 hours. After cooling to ambient temperature, CH₃ I (0.3ml) was added, and then the reaction was poured into H₂ O. The aqueousreaction mixture was extracted with ethyl acetate, the extract washed(H₂ O), dried (MgSO₄) and the solvent was concentrated to an oil, whichsolidified to give 6.8 g of a solid. The solid was chromatographed on asilica gel column utilizing flash chromatography (50 mm diameter;eluting with CH₂ Cl₂ /acetone, 6:4). Evaporation of the appropriatefractions yielded 4.2 g of a solid. Recrystallization of the solid fromisopropyl alcohol gave 3.6 g (45%) of1-acetyl-4-(6-methylthio-1-phenyl-1H-indazol-3-yl)piperidine, mp120°-122° C.

Analysis: Calculated for C₂₁ H₂₃ N₃ OS: 69.02%C, 6.34%H, 11.50%N. Found:69.12%C, 6.44%H, 11.56%N.

EXAMPLE 95 (a) 1-Acetyl-4-(2,4-dichlorobenzoyl)piperidinephenylhydrazone

A stirred mixture of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine (33.0g., 0.11 mol.), phenylhydrazine hydrochloride (34.2 g) and anhydroussodium acetate in isopropanol was refluxed for 2 hours. The reaction wasstirred overnight (about 16 hours) at ambient temperature. The reactionwas filtered and the filter cake was washed with ether and thendispersed into water. The water insoluble solid was collected and driedto yield 21.3 g of the product, mp 209°-211° C. Concentration of thefiltrate afforded an oil which on standing one week partiallysolidified. The resultant mixture was triturated with CH₃ CN and anadditional 7.5 g of the product1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone was obtained.

(b) 1-Acetyl-4-(6-chloro-1-phenyl-1H-indazol-3-yl)piperidine

To a stirred solution, under nitrogen of potassium tert-butoxide (6.5 g,0.06 mol) in THF (250 ml) was added, portionwise,1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone (19.3 g,0.049 mol) of Example 95 (a). The solution was refluxed for 5 hours andthen poured into H₂ O. The aqueous mixture was extracted with ethylacetate, the ethyl acetate washed (H₂ O), dried (MgSO₄) and the solventconcentrated to yield an oil. The oil, upon being scratched with a glassrod, solidified to yield 16.4 g (95%) of a solid. A 5.0 g sample of thesolid was chromatographed utilizing flash chromatography on a silica gelcolumn, and eluting with CH₂ Cl₂ -acetone (30%). Upon evaporation of theappropriate fractions, there remained 4.3 g of a solid mp 128°-130° C.Recrystallization of the solid from ethyl acetate-hexane yielded 3.4 gof 1-acetyl-4-(6-chloro-1-phenyl-1H-indazol-3-yl)piperidine, mp130°-132° C.

Analysis: Calculated for C₂₀ H₂₀ ClNO₃ : 67.88%C, 5.70%H, 11.78%N.Found: 67.92%C, 6.00%H, 11.83%N.

EXAMPLE 96 3-(1-Benzoyl-4-piperidinyl)-6-fluoro-1-phenyl-1H-indazole

To a stirred mixture of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazoleof Example 98(b) (3.5 g, 0.012 mol), K₂ CO₃ (2.0 g) in toluene (15 ml)--CHCl₃ (15 ml) was added, dropwise, benzoyl chloride (2.3 g, 0.016mol). The reaction was stirred and refluxed for 2 hours, and then pouredinto H₂ O. The organic layer was separated, the aqueous layerre-extracted with CHCl₃ and the combined organic phase dried (MgSO₄).Upon concentration of the organic phase, there remained an oil, whichsolidified upon standing. The solid was triturated with cyclohexane andfiltered to yield 4.6 g of product. Recrystallization from ethanol-H₂ Oyielded 3.2 g (67%) of3-(1-benzoyl-4-piperidinyl)-6-fluoro-1-phenyl-1H-indazole, mp 149°-151°C.

Analysis: Calculated for C₂₅ H₂₂ FN₃ O: 75.14%C, 5.55%H, 10.52%N. Found:75.08%C, 5.62%H, 10.48%N.

EXAMPLE 97 6-Bromo-1-phenyl-3-(4-piperidinyl)-1H-indazole Hydrochloride

A mixture of 1-acetyl-4-(6-bromo-1-phenyl-1H-indazol-3-yl)piperidine ofExample 92(b) (8.5 g, 0.02 mol) and 6N HCl (40 ml) was stirred andrefluxed for 5 hours. The reaction was then stirred at ambienttemperature for 8 hours and a solid was precipitated from solution. Thesolid was collected, washed with water and acetone, and dried undervacuum to yield 7.5 g of product. An analytical sample was obtained byrecrystallization of a 4.0 g sample twice from ethanol, and thisafforded 2.3 g (57%) of 6-bromo-1-phenyl-3-(4-piperidinyl)-1H-indazolehydrochloride, mp 225°-257° C.

Analysis: Calculated for C₁₈ H₁₈ BrN₃.HCl: 55.11%C, 4.88%H, 10.71%N.Found: 54.77%C, 4.75%H, 10.58%N.

EXAMPLE 98 6-Fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole Hydrochloride

A mixture of 1-acetyl-4-(6-fluoro-1-phenyl-1H-indazol-3-yl)piperidine ofExample 39 (8.0 g, 0.024 mol) and 6N HCl (50 ml) was stirred andrefluxed for 4 hours. After cooling to ambient temperature, the mixturewas diluted with H₂ O, cooled in an ice bath, stirred, and dilute,aqueous NaOH was added dropwise, until the mixture was basic. Themixture was extracted with ethyl acetate, the extract washed (H₂ O),dried (MgSO₄) and the solvent was concentrated in vacuo to yield 7.5 gof an oil. The oil was dissolved in ethyl acetate, and HCl (g) wasdischarged into the solution to precipitate 5.9 g of a whitehydrochloride salt. The salt was recrystallized from isopropanol-etherto yield 4.6 g (58%) of product. An analytical sample was obtained byrecrystallizing a 3.0 g sample again from isopropyl alcohol to yield 2.5g of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole hydrochloride, mp213°-215° C.

Analysis: Calculated for C₁₈ H₁₈ FN₃.HCl: 65.28%C, 5.78%H, 12.69%N.Found: 65.41%C, 5.79%H, 12.44%N.

EXAMPLE 99 4-(1-Phenyl-1H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester

A mixture of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile ofExample 73 (4.0 g, 0.013 moles) and sodium methoxide (3 ml of 25% sodiummethoxide in methanol, 0.013 moles) in methanol (30 ml) was warmed toeffect solution and then stirred at ambient temperature for 16 hours.The solvent was removed which left an oil (4.5 g). The oil was dissolvedin ether, washed with H₂ O, and dried (MgSO₄). Removal of the ether leftan oil which began to crystallize upon standing. Crystallization wasenhanced by triturating the oil with hexane which produced 3.5 g ofproduct. The product was recrystallized twice from hexane yielding 2.31g (52%) of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carboximidic acidmethyl ester, mp 80°-83° C.

Analysis: Calculated for C₂₀ H₂₂ N₄ O: 71.83%C, 6.63%H, 16.75%N. Found:71.76%C, 6.77%H, 16.75%N.

EXAMPLE 100N-Methyl-4-[1-(2-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxamide

A stirred mixture of4-[1-(2-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 74 (32.7 g, 0.102 moles) and 25% H₂ SO₄ (300 ml) was refluxedfor 20 hours. The mixture was then cooled, poured into H₂ O and basifiedwith 25% NaOH solution. The product was extracted with dichloromethane,dried (MgSO₄), and concentrated which yielded 28 g of an oil. The oilwas triturated with acetone to produce 14 g of the solid amine product(47%). To a suspension of the amine (8.0 g, 0.027 moles) in toluene (140ml) was added dropwise a solution of methyl isocyanate (3.4 ml, 0.057moles) in toluene (20 ml). The reaction was stirred at ambienttemperature for 2 hours. A small amount of insoluble material wasfiltered off and the filtrate was concentrated to yield 7.2 g of an oil.The oil was chromatographed twice (silica gel, first with ethyl acetateand then with 5% methanol-CHCl₃), which yielded 3.5 g of a solid. Thesolid was recrystallized twice from acetone-hexane which yielded 2.2 g(23%) ofN-methyl-4-[1-(2-fluorophenyl-1H-indazol-3-yl]piperidine-1-carboxamide,m.p. 131°-133° C.

Analysis: Calculated for C₂₀ H₂₁ FN₄ O: 68.15%C, 6.01%H, 15.90%N. Found:68.44%C, 6.06%H, 16.15%N.

EXAMPLE 1014-[1-[4-(Trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile

To a stirred mixture of cyanogen bromide (14.4 g, 0.136 moles) andpotassium carbonate (22.1 g, 0.16 moles) in dimethylsulfoxide (270 ml)was added dropwise3-(1-methyl-4-piperidinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole(45.78 g, 0.127 moles), the free base of example 9, dissolved in hotdimethylsulfoxide (250 ml). The reaction was stirred at ambienttemperature for 19 hours and was then poured into H₂ O and extracted(CH₂ Cl₂). The organic layer was dried (MgSO₄) and concentrated to yield34.5 g of product. The product was recrystallized three times fromisopropyl alcohol to yield 18.6 g (39%) of4[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile,mp 135°-136° C.

Analysis: Calculated for C₂₀ H₁₇ F₃ N₄ : 64.86%C, 4.63%H, 15.13%N.Found: 64.68%C, 4.57%H, 15.01%N.

EXAMPLE 1024-[1-(4-Fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile

To a stirred mixture of cyanogen bromide (21.67 g, 0.204 moles) andpotassium carbonate (33.2 g, 0.24 moles) in dimethyl sulfoxide (400 ml)was added dropwise a solution of1-(4-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole (59.45 g,0.192 moles), the free base of example 67, in hot dimethyl sulfoxide(375 ml). The reaction was stirred at ambient temperature for 4 days andthen poured into H₂ O (500 ml). The product was extracted(dichloromethane), dried (MgSO₄), and concentrated to yield 64 g of asolid. The product was recrystallized twice from isopropyl alcohol yield35.7 g (58%) of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, mp108°-110° C.

Analysis: Calculated for C₁₉ H₁₇ FN₄ : 71.23%C, 5.35%H, 17.49%N. Found:71.24%C, 5.34%H, 17.45%N.

EXAMPLE 1034-[1-(2-Cyanophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile

To a stirred mixture of cyanogen bromide (7.16 g, 0.068 moles) andpotassium carbonate (10.96 g, 0.079 moles) in dimethylsulfoxide (130 ml)was added dropwise a solution of1-(2-cyanophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole of Example 109(20.0 g, 0.063 moles) in hot (120 ml). The reaction was stirred atambient temperature for 3 hours and then poured into H₂ O. The productwas extracted (CHCl₃), dried (MgSO₄), and concentrated to yield 18 g ofa solid. The product was recrystallized twice from CHCl₃ -hexane andonce from acetone-hexane to yield 12.0 g (58%) of4-[1-(2-cyanophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, m.p.188°-190° C.

Analysis: Calculated for C₂₀ H₁₇ N₅ : 73.37%C, 5.23%H, 21.39%N. Found:73.47%C, 5.49%H, 21.41%N.

EXAMPLE 104 6-Bromo-1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazoleHydrochloride Sesquihydrate

A mixture of 6-bromo-3-(1-methyl-4-piperidinyl)-1H-indazole of Example106(b) (3.0 g, 0.01 mol) and benzoyl chloride (8 ml) was heated at 100°C. (steam bath) for 2 hours. After the reaction had cooled, ether wasadded and 4.3 g of a hydrochloride salt was collected. After tworecrystallizations from methanol-ether failed to purify the compoundadequately, the compound was converted to its free base (2.0 g), andcombined with 1.7 g of a sample from another run. The combined samplewas then dissolved in ether and the hydrochloride salt was formed by theaddition of ethereal HCl. The resulting salt (3.7 g) was recrystallizedfrom ethanol-ether to yield 2.2 g (28%) of6-bromo-1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloridesesquihydrate, mp 271°-273° C.

Analysis: Calculated for C₂₀ H₂₀ BrN₃ O.HCl.1.5H₂ O: 52.02%C, 5.24%H,9.10%N. Found: 52.14%C, 4.89%H, 9.10%N.

EXAMPLE 105 3-(1-Methyl-4-piperidinyl)-5-nitro-1H-indazole

To a stirred, cooled (ca.5° C.) solution of3-(1-methyl-4-piperidinyl)-1H-indazole (10.7, 0.05 mol) of Example 4 in83% H₂ SO₄ (60 ml) was added, dropwise, concentrated HNO₃ (29 ml, 0.46mol, sp. gr. 1.42) at such a rate so that the temperature of thereaction did not rise above 35° C. After complete addition of the nitricacid, the cooling bath was removed and the reaction was allowed toproceed at ambient temperature for 16 hours. The resultant solution waspoured onto ice, and almost immediately a solid formed. The solid wasfiltered and after drying in a vacuum oven there remained 10.3 g of asalt, mp 263°-265° C. The compound was partially dissolved in warm H₂ Oand NH₄ OH was added until the mixture was basic. The resulting solidwas collected and dried to yield 7.4 g of product, mp 235°-237° C.Recrystallization (twice) from ethanol-H₂ O yielded 3.8 g (29%) of3-(1-methyl-4-piperidinyl)-5-nitro-1H-indazole, mp 237°-239° C.

Analysis: Calculated for C₁₃ H₁₆ N₄ O₂ : 59.98%C, 6.20%H, 21.53%N.Found: 60.27%C, 6.27%H, 21.35%N.

EXAMPLE 106 (a) 4-(6-Bromo-1H-indazol-3-yl)piperidine-1-carboxylic acidmethyl ester

To a stirred mixture of the 6-bromo-3-(4-piperidinyl)-1H-indazole (23.3g, 0.083 mol), NaHCO₃ (30.6 g, 0.36 mol) in CHCl₃ (125 ml)--THF (125 ml)was added methyl chloroformate (27.9 ml, 34.1 g, 0.36 mol) in a dropwisemanner. The mixture was stirred at ambient temperature for 16 hours. Thereaction was poured into H₂ O, and the organic layer was separated. Theorganic phase was dried (K₂ CO₃) and the solution concentrated in vacuoto yield 42.6 g of an oil. The crude oil was dissolved in 200 ml ofmethanol and 6 ml of a 25% sodium methoxide in methanol added. Theresultant solution was stirred at ambient temperature for 2 hours andthen most of the methanol was removed in vacuo to leave a gum. The gumwas diluted in H₂ O and extracted with CH₂ Cl₂. After washing (brine)and drying (K₂ CO₃) concentration of the organic layer gave 8.4 g ofproduct.

(b) 6-Bromo-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred suspension of LiAlH₄ (6.2 g, 0.083 mol of a 50-55% oildispersion) in THF (175 ml), under nitrogen, was added, dropwise,4-(6-bromo-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester(28.1 g, 0.083 mol) of Example 106 (a). The reaction was refluxed for 1hour, cooled in an ice bath, and water was added. The reaction wasfiltered and the filtrate was concentrated to yield 13.5 g of a solid.The solid was recrystallized from toluene to yield 10.2 g (42%) of asolid, mp 203°-205° C. An analytical sample was obtained bychromatography of a 3.4 g sample on a preparative HPLC (silica gelcolumn) utilizing CH₂ Cl₂ --CH₃ OH--(C₂ H₅)₂ NH (95:4:1) as eluent.After evaporation of the appropriate fractions there remained 2.8 g of6-bromo-3-(1-methyl-4-piperidinyl)-1H-indazole, mp 205°-207° C.

Analysis: Calculated for C₁₃ H₁₆ BrN₃ : 53.07%C, 5.48%H, 14.28%N. Found:53.17%C, 5.97%H, 14.38%N.

EXAMPLE 107 1-(2-Methoxyphenyl)-3-(1-methyl-4-piperidinyl)-1H-indazolefumarate

A mixture of 4-(2-fluorobenzoyl)-1-methylpiperidine (14.6 g. 0.066moles) of Example 1, 2-methoxyphenylhydrazine hydrochloride (14.5 g,0.083 moles) and sodium acetate (16.0 g, 0.195 moles) in n-butanol (280ml) was refluxed for 7 hours. The mixture was cooled, filtered, and thenconcentrated to yield 22 g (100%) of an oil. To a solution of the oil(21.6 g, 0.063 moles) in DMF (220 ml) was added NaH (6.7 g, 0.139 moles,50% oil dispersion). The mixture was stirred at 80° C. for 3 hours andthen cooled and poured into H₂ O. The aqueous mixture was extracted withethyl acetate, dried (MgSO₄) and concentrated to yield 22 g of an oil. Aportion of the oil (9.5 g) was purified using HPLC (silica gel, 100%methanol) to yield 4.5 g of an oil. The oil was dissolved in ether and asolution of fumaric acid in ether was added to form a salt. The salt wasrecrystallized three times from ethanol-ether to yield 2.15 g (15%) of1-(2-methoxyphenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole fumarate,m.p. 177°-178° C.

Analysis: Calculated for C₂₀ H₂₃ N₃ O.C₄ H₄ O₄ : 65.94%C, 6.21%H,9.59%N. Found: 65.87%C, 6.34%H, 9.57%N.

EXAMPLE 108 1-Benzoyl-3-(1-methyl-4-piperidinyl)-5-nitro-1H-indazoleHydrochloride

A mixture of 3-(1-methyl-4-piperidinyl)-5-nitro-1H-indazole (4.0 g,0.015 mol) of Example 105 and benzoyl chloride (12 ml) was heated at100° C. (steam bath) for 4 hours. After cooling to ambient temperature,ether was added, the mixture stirred for 1 hour and then 4.9 g of asolid was collected. The solid was recrystallized twice from DMF andonce from methanol to yield 2.3 g (38%) of1-benzoyl-3-(1-methyl-4-piperidinyl)-5-nitro-1H-indazole hydrochloride,mp 297°-299° C.

Analysis: Calculated for C₂₀ H₂₀ N₄ O₃.HCl: 59.91%C, 5.28%H, 13.97%N.Found 59.96%C, 5.31%H, 14.11%N.

EXAMPLE 109 1-(2-Cyanophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole

To a stirred suspension of NaH (19.6 g, 0.41 moles, 50% oil dispersion)in DMF (150 ml) was added dropwise a solution of3-(1-methyl-4-piperidinyl)-1H-indazole (40.0 g, 0.186 moles) of Example4 in hot DMF (300 ml). The mixture was stirred for 1 hour at ambienttemperature and then 2-fluorobenzonitrile (22.2 ml, 0.20 moles) wasadded. The mixture was stirred at ambient temperature for 4 hours andthen poured into H₂ O. The product was extracted (ethyl acetate), dried(MgSO₄), and concentrated to yield 46 g of a solid. The product wasrecrystallized twice from isopropyl alcohol which yielded 27.0 g (46%)of 1-(2-cyanophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole, mp117°-119° C.

Analysis: Calculated for C₂₀ H₂₀ N₄ : 75.92%C, 6.37%H, 17.71% N. Found:75.94%C, 6.29%H, 17.66%N.

EXAMPLE 110 2-[3(1-Methyl-4-piperidinyl)-1H-indazol-1-yl]benzamide

To a stirred suspension of NaH (4.0 g, 0.083 mol of a 50% oildispersion) in DMF (100 ml), under nitrogen, was added, dropwise,3-(1-methyl-4-piperidinyl)-1H-indazole (15.0, 0.07 mol) of Example 4dissolved in hot DMF (100 ml). The reaction was stirred at ambienttemperature for 0.75 hour and then 2-fluorobenzamide (11.6 g, 0.083 mol)was added dissolved in DMF (50 ml). The temperature of the reaction wasthen raised to 80° C. and kept there for 16 hours. The reaction waspoured into H₂ O, and the resulting solid which formed was collected anddried to yield 17.7 g. Subsequent extractive workup of the aqueousfiltrate with ethyl acetate yielded an additional 2.5 g of the compound.The samples were combined and recrystallized from ethyl acetate and thenfrom ethanol-water to yield 14.1 g (60%) of product mp 185°-187° C. Ananalytical sample was obtained by an additional recrystallization of a3.0 g sample from ethanol-water which resulted in 2.3 g of2-[3-(1-methyl-4-piperidinyl)-1H-indazol-1-yl]benzamide.

Analysis: Calculated for C₂₀ H₂₂ N₄ O: 71.83%C, 6.63%H, 16.75%N. Found:71.90%C, 6.73%H, 16.72%N.

EXAMPLE 111 (a) 4-(2,5-difluorobenzoyl)-1-methylpiperidine

To a stirred suspension of Mg (9.62 g, 0.40 moles) in tetrahydrofuran(THF) (45 ml) was added a few ml of bromoethane to initiate the reactionfollowed by dropwise addition of freshly distilled4-chloro-N-methylpiperidine (42.3 g, 6.32 moles) in THF (140 ml). Thereaction was initiated with a high intensity heat gun and controlled bythe rate of addition of the piperidine. After the addition was complete,the reaction was refluxed for 1 hour. Next 2,5-difluorobenzonitrile(48.2 g, 0.318 moles) in THF (20 ml) was added and the reaction wasrefluxed for an additional 3 hours. The reaction was allowed to standfor 65 hours and was then poured into a solution of NH₄ Cl/H₂ O (120g/400 ml). The mixture was heated on a steam bath for 2 hours, cooledand extracted with ether (500 ml.). Concentration produced an oil (50.6g) which the product was distilled from (112° C. @ 0.5 mm) to yield 30.4g (40%) of the product.

(b) 5-fluoro-1-phenyl-3-(1-methyl-4-piperidinyl)-1H-indazoleHydrochloride

A stirred mixture of 4-(2,5-difluorobenzoyl)-1-methylpiperidine (23.4 g,0.098 moles), phenyl hydrazine hydrochloride (28.2 g, 0.196 moles) andsodium acetate (32.1 g, 0.392 moles) in ethanol (180 ml) was refluxedfor 5 hours. The mixture was stirred overnight (about 16 hours) atambient temperature and then filtered. The solid which was collected waswashed with H₂ O and then ether to yield 10.4 g of the hydrazone. Thefiltrate was concentrated and washed with ether to yield an additional12.9 g of the hydrazone giving a total of 23.3 g (72%) of hydrazone,m.p. 146°-150° C. To a solution of the hydrazone (23.0 g, 0.070 moles)in DMF (230 ml) was added NaH (7.4 g, 0.154 moles, 50% oil dispersion).The mixture was stirred at 80° C. for 2 hours and then cooled and pouredinto H₂ O. The aqueous mixture was extracted (ethyl acetate), dried(MgSO₄) and concentrated to yield 15.2 g of an oil. The hydrochloridesalt was formed by dissolving a portion (4.0 g) of the oil in ether andadding ethereal HCl. The salt was washed with ether and recrystallizedonce from ethanol-ether and then once from isopropyl alcohol-hexane toyield 2.3 g (36%) of5-fluoro-1-phenyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride,m.p. 270°-272° C.

Analyses: Calculated for C₁₉ H₂₀ FN₃.HCl: 65.99%C, 6.12%H, 12.15%N.Found: 65.92%C, 6.04%H, 12.20%N.

EXAMPLE 1123-(1-Methyl-4-piperidinyl)-1-(2,3,4,5,6-pentafluorophenyl)-1H-indazoleHydrochloride Hemihydrate

To a solution of 4-(2-fluorobenzoyl)-1-methylpiperidine (27.7 g, 0.125mol) free base of example 1 in diethyl phosphite (50 ml) was added asolution of pentafluorophenylhydrazine (27.7 g, 0.14 mol) in diethylphosphite (70 ml). The reaction was heated on a steam bath for 2 hoursand then poured into H₂ O. The aqueous solution was made basic with NH₄OH, and the phenylhydrazone was deposited as an oil. The supernatantaqueous was separated from the oil, and the oil was taken up in ether.The ether was washed twice with H₂ O, dried (MgSO₄) and the solvent wasconcentrated to yield 48.2 of the pentafluorophenylhydrazone as an oil.To a stirred solution, under nitrogen, of the obtained4-(2-fluorobenzoyl)-1-methylpiperidine pentafluorophenylhydrazone (46.5g, 0.12 mol), in THF (500 ml), was added dropwise a solution ofpotassium tert-butoxide (15.2 g, 0.14 mol) in THF (400 ml). Aftercomplete addition of the alkoxide, the reaction was stirred at ambienttemperature for 16 hours, and then poured into H₂ O. The aqueous mixturewas extracted with ether, the ether washed (H₂ O) dried (MgSO₄) and thesolvent was concentrated to yield 45.1 g of an oil. The oil waschromatographed on a Waters Prep 500 utilizing silica gel columns andeluting with ethyl acetate-diethylamine (10%). Concentration of theappropriate fractions yielded 10.9 g of the desired indazole as anuncrystallizable oil. The compound was converted to a hydrochloride saltwith ethereal HCl to yield 9.1 g (17%) of a solid. The solid wasrecrystallized twice from CH₃ CN to yield 3.0 g of3-(1-methyl-4-piperidinyl)-1-(2,3,4,5-pentafluorophenyl)-1H-indazolehydrochloride hemihydrate, mp 249°-251° C.

Analysis: Calculated for C₁₉ H₁₆ F₅ N₃.HCl.0.5H₂ O: 53.46%C, 4.25%H,9.85%N. Found: 53.33%C, 4.02%H, 9.85%N.

EXAMPLE 1134-[1-(4-Fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxylic acidmethyl ester

A stirred mixture of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile ofExample 102 (30 g, 0.094 moles) and 25% H₂ SO₄ (225 ml) was refluxed for20 hours. The mixture was cooled, poured into H₂ O, and basified with a25% NaOH solution. The product was extracted (dichloromethane), dried(MgSO₄), and concentrated to yield 21 g (76%) of1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirredsuspension of the indazole (3.5 g, 0.012 moles) and triethylamine (3.3ml, 0.024 moles) in toluene (50 ml) was added methyl chloroformate (1.0ml, 0.013 moles). The mixture was stirred for 17 hours at ambienttemperature and was poured into H₂ O. The product was extracted (ethylacetate), dried (MgSO₄), and concentrated to yield 4.6 g of an oil. Theproduct was purified on the HPLC (silica gel:ethyl acetate-hexane, 1:2)which produced 3.0 g (72% of4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxylic acidmethyl ester, m.p. 95°-97° C.

Analysis: Calculated for C₂₀ H₂₀ F₁ N₃ O₂ : 67.97%, 5.70%H, 11.89%N.Found: 67.71%C, 6.02%H, 11.93%N.

EXAMPLE 1143-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-6-fluoro-1-phenyl-1H-indazole

A stirred mixture, under nitrogen, of6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole (1.5 g, 0.005 mol), thefree base of Example 98, 4-chloro-1,1-bis-(4-fluorophenyl)butane (1.6 g,0.0056 mol), Na₂ CO₃ (0.6 g), a few crystals of KI and4-methyl-2-pentanone (70 ml) was refluxed for 16 hours. The reaction waspoured into H₂ O, and the aqueous mixture extracted with ethyl acetate.The ethyl acetate was washed (H₂ O), dried (MgSO₄) and the solvent wasconcentrated to a liquid. The liquid was dissolved in anhydrous etherand HCl (g) was added to precipitate a gum. The supernatant ether wasdecanted, H₂ O was added to the gum, and the mixture was made basic withNH₄ OH. The basic suspension was extracted with ether, the extractwashed (H₂ O), dried (MgSO₄), and the solvent was concentrated to yield0.64 g (24%) of a solid. This material was combined with 2.9 g of acompound from another run and recrystallized from isopropyl ether toyield 2.1 g of3-[1-[4,4-bis(4-fluorophenyl)butyl-4-piperidinyl]-6-fluoro-1-phenyl-1H-indazole,mp 113°-115° C.

Analysis: Calculated for C₃₄ H₃₂ F₃ N₃ : 75.67%C, 5.98%H, 7.79%N. Found:75.99%C, 6.20%H, 7.76%N.

EXAMPLE 115 1-[4-(Trifluoromethyl)phenyl]-3-[1-(dimethylphosphinylmethyl)-4-piperidinyl]-1H-indazole

A stirred mixture of4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1carbonitrileof Example 101 (15 g, 0.041 moles) and 25% H₂ SO₄ (100 ml) was refluxedfor 20 hours. The mixture was cooled, poured into H₂ O, and basifiedwith a 25% NaOH solution. The product was extracted (dichloromethane),dried (MgSO₄), and concentrated to yield 13 g (93%) of1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. Astirred mixture of the indazole (4.0 g, 0.012 moles), potassiumcarbonate (3.6 g, 0.026 moles) and chloromethyldimethyl phosphine oxide(3.96 g, 0.031 moles) in DMF (30 ml) was heated at 80° C. for 40 hours.The mixture was cooled, poured into H₂ O, extracted (CHCl₃), dried(MgSO₄) and concentrated to yield 4.8 g of an oil. The product waspurified on the HPLC (silica gel, 5% methanol-CHCl₃) and thenrecrystallized once from acetone-hexane to yield 2.2 g (35%) of1-[4-(trifluoromethyl)phenyl]-3-[1-(dimethylphosphinylmethyl)-4-piperidinyl]-1H-indazole, m.p. 158°-160° C.

Analysis: Calculated for C₂₂ H₂₅ F₃ N₃ OP: 60.69%C, 5.79%H, 9.65%N.Found: 60.59%C, 5.87%H, 9.68%N.

EXAMPLE 1164-(5-Fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile

To a stirred mixture of cyanogen bromide (4.05 g, 0.038 moles) andpotassium carbonate (6.2 g, 0.045 moles) in dimethylsulfoxide (75 ml)was added dropwise a solution of5-fluoro-1-phenyl-3-(1-methyl-4-piperidinyl)-1H-indazole (11.0 g, 0.036moles) free base of Example 111(b) in hot dimethylsulfoxide (75 ml). Thereaction was stirred at ambient temperature for 28 hours and then pouredinto water. The product was extracted (dichloromethane), dried (MgSO₄)and concentrated to yield 10.8 g of an oil which crystallized uponstanding. The product was recrystallized twice from isopropylalcohol-ether and once from isopropyl alcohol which yielded 3.8 g (33%)of the 4-(5-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile,m.p. 137°-139°.

Analysis: Calculated for C₁₉ H₁₇ FN₄ : 71.23%C, 5.35%H, 17.49%N. Found:71.08%C, 5.52%H, 17.57%N.

EXAMPLE 1174-[1-[2-(Aminocarbonyl)phenyl-1H-indazol-3-yl]piperidine-1-carboximidicacid methyl ester

A mixture of 2-[3-(1-cyano-4-piperidinyl)-1H-indazol-1-yl]benzamide (9.7g, 0.024 mol) methanol (150 ml) and 25% sodium methoxide (5.5 ml) washeated to reflux until solution was effected. The reaction was thenstirred at ambient temperature for 16 hours. The solvent wasconcentrated and the residue was treated with water. The resulting gumwas scratched with a glass rod to induce crystallization, and 9.8 g of asolid were collected. The compound was recrystallized from ethanol-waterto yield 5.7 g (52.6) of product. An analytical sample was obtained byrecrystallization of a 3.0 sample again from ethanol-water to yield 2.2g of4-[1-[2-(aminocarbonyl)phenyl-1H-indazol-3-yl]piperidine-1-carboximidicacid methyl ester, mp 192°-194°.

Analysis: Calculated for C₂₁ H₂₃ N₅ O₂ : 66.80%C, 6.14%H, 18.56%N.Found: 66.93%C, 6.30%H, 18.49%N.

EXAMPLE 118 1-(4-Aminophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole

A solution of 1-(4-nitrophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole(20.0 g, 0.060 moles) in dimethylformamide (300 ml) was added to a 5%palladium on carbon catalyst (1 g). The reduction was carried out onParr hydrogenation apparatus using an initial pressure of 50 psi of H₂,until the uptake of H₂ ceased. The catalyst was filtered from thesolution and the solvent was removed which produced 20 g of an oil. Theproduct was purified using high pressure liquid chromatography (silicagel, 5% diethylamine-ethyl acetate to yield 10.65 g of a solid. Thesolid was recrystallized twice from acetone-hexane to yield 6.6 g (36%)of 1-(4-aminophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole, m.p.116°-118°.

Analysis: Calculated for C₁₉ H₂₂ N₄ : 74.48%C, 7.24%H, 18.28%N. Found:74.53%C, 7.46%H, 18.39%N.

EXAMPLE 1191-Formyl-4-[6-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine

To a stirred suspension, under N₂, of NaH (5.8 g, 0.12 mol, of a 50% oildispersion) in dimethylformamide (DMF) (100 ml) was added, dropwise,1-formyl-4-(6-fluoro-1H-indazoyl-3-yl)piperidine (25.3 g, 0.094 mol)dissolved in DMF (175 ml). After stirring at ambient temperature for 45minutes, p-fluorobenzotrifluoride (192 g, 0.12 mol) was added dissolvedin DMF (175 ml). After stirring at ambient temperature for 45 minutes,p-fluorobenzotrifluoride (192 g, 0.12 mol) was added dissolved in DMF(20 ml). The temperature was then raised to 83°-85° and stirring wascontinued at this temperature for 16 hours. The reaction was poured intoH₂ O, and the aqueous mixture was extracted with ethyl acetate. Theorganic layer was washed (H₂ O), dried (MgSO₄) and the solvent wasconcentrated to yield 38.4 g of an oil. The oil was combined with a 3.8g sample from another run and chromatographed on a Water's Prep 500 HPLCutilizing silica gel columns and eluting with CH₂ Cl₂ /methanol (2%).Concentration of the appropriate fractions yielded 25 g (61%) of theindazole. Recrystallization of 4.0 g from isopropanol-H₂ O yielded 3.4 gof1-formyl-4-[6-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine,mp 142°-144°.

Analysis: Caculated for C₂₀ H₁₇ F₄ N₃ O: 61.38%C, 4.38%H, 10.74%N.Found: 61.15%C, 4.45%H, 10.68%N.

EXAMPLE 1204-[6-Fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide

To a solution of6-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole(4.0 g, 0.11 mol) in DMF was added nitrourea (2.6 g, 0.04 mol). Almostimmediately, a solid precipitated from solution, and the reaction wasthen heated on a steam bath to effect solution (gas evolution). Afterstanding for 1 hour at ambient temperature, the reaction was poured intoH₂ O, and the aqueous mixture was extracted with ethyl acetate. Theethyl acetate extract was washed (H₂ O), dried (MgSO₄) and the solventconcentrated to yield 4.2 g of a solid. This material was combined withanother sample (1.2 g) and the combined sample chromatographed with aWater's Prep 500 on silica gel columns. The desired product was elutedwith CH₂ Cl₂ -methanol (4%), and after concentration of the appropriatefractions, the product was isolated as a solid. The solid was trituratedwith ether and 3.5 g of the urea was collected. Recrystallization frommethyl acetate-hexane yielded 2.7 g (48%) of4-[6-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide,m.p. 148°-150°.

Analysis: Calculated for C₂₀ H₁₈ F₄ N₄ O: 59.09%C, 4.46%H, 13.78%N.Found: 59.09%C, 4.64%H, 13.76%N.

EXAMPLE 121 5-Fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole

A mixture of 4-(2,5-difluorobenzoyl)-1-methylpiperidine of Example 111(38.5 g, 0.16 moles) and hydrazine monohydrate (79.5 g, 1.59 moles) washeated in an autoclave at 150° for 22 hours. The autoclave was cooled inan ice bath and then opened. The reaction mixture was poured into H₂ O,causing the product to crystallize. The product was collected and thenrecrystallized twice from toluene to yield 8.2 g (22%) of5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole, m.p. 202°-204°.

Analysis: Calculated for C₁₃ H₁₆ FN₃ : 66.93%C, 6.91%H, 18.01%N. Found:66.82%C, 6.88%H, 18.07%N.

EXAMPLE 1225-Fluoro-1-[4-(trifluoromethyl)phenyl]-3-(1-methyl-4-piperidinyl)-1H-indazole

To a suspension of NaH (4.1 g, 0.085 moles, 50% oil dispersion) in DMF(110 ml) was added a solution of5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (16.5 g, 0.071 moles) inhot DMF (110 ml). The mixture was stirred at ambient temperature for 1hour and then 4-fluorobenzotrifluoride (10.6 ml, 0.084 moles) was added.The reaction was heated at 90° for 20 hours and then cooled and pouredinto H₂ O. The product was extracted (ethyl acetate), dried (MgSO₄), andconcentrated to yield 21.5 g of an oil. The product was purified by highpressure liquid chromatography (silica gel, 3% diethylamine-ethylacetate) to yield 17.8 g of product. The product was triturated withhexane to yield 15.5 g (58%) of5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(1-methyl-4-piperidineyl)-1H-indazole,m.p. 126°-128°.

Analysis: Calculated for C₂₀ H₁₉ F₄ N₃ : 63.65%C, 5.07%H, 11.13%N.Found: 63.43%C, 5.03%H, 11.26%N.

EXAMPLE 1236-Fluoro-3-(4-piperidinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazoleHydrochloride

A mixture of6-fluoro-3-(1-formyl-4-piperidinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole(9.5 g, 0.024 mol), 3N HCl (90 ml) and ethanol (90 ml) was stirred andrefluxed for 3 hours. After stirring at ambient temperature for 11hours, the reaction mixture was diluted with H₂ O, cooled in an icebath, and was made basic by the dropwise addition of 25% aqueous NaOH.The basic mixture was extracted with ethyl acetate, the extract washed(H₂ O), dried (MgSO₄) and the solvent was concentrated to yield 7.0 g(80%) of a solid. A 2.4 g sample was removed, dissolved in ethanol-etherand an ethereal solution of HCl was added to precipitate 2.4 g of ahydrochloride salt. Recrystallization from isopropyl alcohol-etheryielded 1.5 g of6-fluoro-3-(4-piperidinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazolehydrochloride, mp 231°-233°.

Analysis: Calculated for C₁₉ H₁₇ F₄ N₃.HCl: 57.13%C, 4.52%H, 10.52%N.Found: 56.86%C, 4.54%H, 10.57%N.

EXAMPLE 1245-Fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazoleHydrochloride

To a solution of5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(1-methyl-4-piperidinyl)-1H-indazole(13.2 g, 0.035 moles) in 1,2-dichloroethane (35 ml) at 0° C. was added1-chloroethylchloroformate (3.9 ml, 0.035 moles). The reaction wasstirred for 15 minutes at 0° and then for 4 hours at ambienttemperature. The solvent was removed and then methanol (90 ml) wasadded. The mixture was refluxed for 1 hour and then the methanol wasremoved which left 17.8 g of a solid. The product was recrystallizedtwice from isopropyl alcohol to yield 6.3 g (45%) of5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazolehydrochloride, mp 276°-278°.

Analysis: Calculated for C₁₉ H₁₇ F₄ N₃.HCl: 57.08%C, 4.54%H, 10.51%N.Found: 57.15%C, 4.44%H, 10.59%N.

EXAMPLE 1254-[6-Fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-acetamide

A mixture of6-fluoro-3-(4-piperidinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazolefree base of Example 123 (6.2 g, 0.017 mol), 2-chloroacetamide (1.7 g,heated at 90° C. for 0.75 hours. The reaction was poured into H₂ O, andafter standing at ambient temperature for 2 hours, 5.1 g of a solid wascollected. The solid was flash chromatographed [silica gel:CH₂ Cl₂/methanol (5%)] to yield an oil which upon trituration with ether gave3.8 g of a solid. Recrystallization from isopropyl alcohol-H₂ O yielded3.6 g (50%) of4[6-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-acetamide,mp 174°-176°.

Analysis: Calculated for C₂₁ H₂₀ F₄ N₄ O: 59.99%C, 4.80%H, 13.22%N.Found: 59.76%C, 4.86%H, 13.25%N.

EXAMPLE 1264-[5-Fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3yl]piperidine-1-carboxamide

To a solution of5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazolefree base of Example 124 (6.3 g, 0.017 moles) in DMF (100 ml) was addednitrourea (2.2 g, 0.021 moles). The mixture was warmed on a steam bathuntil gas began to evolve and was then stirred at ambient temperaturefor 4 hours. The mixture was then poured into H₂ O and the productextracted (dichloromethane), dried (MgSO₄), and concentrated to yield6.9 of an oil. The oil was triturated with water to produce 6.9 of asolid. The product was purified by high pressure liquid chromatography(silica gel 100% ethyl acetate) followed by recrystallization fromisopropyl alcohol to yield 2.75 g (39%) of4-[5-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide,mp 172°-174°.

Analysis: Calculated for C₂₀ H₁₈ F₄ N₄ O: 59.11%C, 4.46%H, 13.79%N.Found: 58.83%C, 4.46%H, 13.55%N.

I claim:
 1. A compound of the formula ##STR89## wherein R is ##STR90##and R¹ is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkyl,##STR91## diloweralkylaminoloweralkyl, cyano, cyanomethyl, formyl,loweralkanoyl, hydroxymethyl, hydroxyloweralkyl,lowercycloalkylloweralkanoyl, loweralkoxycarbonylloweralkyl, ##STR92##R^(2') is loweralkyl, 2,2,2-trichloroethyl, phenyl or ##STR93## R³ andR⁴ are independently hydrogen or loweralkyl; X, X' and X" areindependently hydrogen, halogen, loweralkyl, loweralkoxy, loweralkanoyl,loweralkylthio, cyano, carbamoyl, hydroxy, nitro, amino ortrifluoromethyl; m is 2 or 3, n is 1 or 2, and the sum of m and n is 3or 4; n' is 2 or 3; p, p' and p" are independently 1 or 2 except when x"is halogen p" is 1 through 5; and q' is 1, 2, 3 or 4; the opticalantipode thereof; or the pharmaceutically acceptable salt thereof.